Patient characteristics
The demographic or clinical characteristics of the patients are presented in Table 1. We identified 400 eligible patients diagnosed with PSC from 2010 to 2016 and 58474 and 33637 patients diagnosed with LADC and LSCC, respectively, in the SEER database. Among the patients with PSC, 31 (7.75%), 194 (48.50%) and 175 (43.75%) patients were aged <50, 51-69 and ≥70 years old at diagnosis, respectively. By comparison, more LADC patients were 51-69 years old (51.95%, P<0.01), and more LSCC patients were aged ≥70 years (51.23%, P<0.01) at diagnosis. Among PSC patients, 58.25% were male, and 41.75% were female, compared to 46.79% of patients who were male and 53.21% of patients who were female among LADC patients and 62.10% who were male and 37.90% who were female among LSCC patients. The majority of PSC patients were white, with tumors located in the upper lobe, and their disease stage was more advanced. In detail, more PSC patients than LSCC patients had stage T3 disease (33.25% vs 23.81%, P<0.01). Moreover, compared to LADC patients, more PSC patients had stage T3 disease, and fewer patients had stage T1 disease (33.25% vs 19.86%, 12.25% vs 28.08%, P<0.01). PSC patients were more frequently diagnosed with N0 and N2 stage disease and less frequently diagnosed with N1 and N2 stage disease. Significantly more PSC patients than LADC patients had stage II and III disease (20.50% vs 8.76%, 22.75% vs 17.74%; P<0.01), and more PSC patients than LSCC patients had stage II and IV disease (20.50% vs 14.66%, 40.25% vs 30.06%; P < 0.001). Approximately half of the PSC patients underwent surgery and chemotherapy, while one-third received radiation. Fewer LADC and LSCC patients were treated with surgery than PSC patients, but they received more radiotherapy.
Table 1. Demographic and clinical characteristics of patients with PSC, LADC and LSCC.
Characteristics
|
PSC
(n = 400)
|
LADC
(n = 58474)
|
LSCC
(n = 33637)
|
Total
(n =92511)
|
P-value*
|
P-value**
|
Age
|
|
|
|
|
<0.01
|
<0.01
|
<50
|
31
|
3140
|
814
|
3985
|
|
|
50-69
|
194
|
30380
|
15591
|
46165
|
|
|
≥70
|
175
|
24954
|
17232
|
42361
|
|
|
Sex
|
|
|
|
|
<0.01
|
0.11
|
Male
|
233
|
27361
|
20888
|
48482
|
|
|
Female
|
167
|
31113
|
12749
|
44029
|
|
|
Race
|
|
|
|
|
0.03
|
<0.01
|
White
|
309
|
42628
|
27992
|
70929
|
|
|
Black
|
64
|
7223
|
3935
|
11222
|
|
|
Others
|
27
|
5623
|
1710
|
7360
|
|
|
Primary Site
|
|
|
|
|
0.11
|
0.01
|
Main bronchus
|
11
|
1262
|
1825
|
3098
|
|
|
Upper lobe
|
253
|
33489
|
18819
|
52561
|
|
|
Middle lobe
|
16
|
2781
|
1239
|
4036
|
|
|
Lower lobe
|
95
|
16247
|
9747
|
26089
|
|
|
Others
|
25
|
4695
|
2007
|
6727
|
|
|
T stage
|
|
|
|
|
<0.01
|
<0.01
|
T0
|
2
|
328
|
85
|
415
|
|
|
T1
|
49
|
16421
|
6465
|
22935
|
|
|
T2
|
127
|
17826
|
11516
|
29469
|
|
|
T3
|
133
|
11611
|
8010
|
19754
|
|
|
T4
|
89
|
12288
|
7561
|
19938
|
|
|
N stage
|
|
|
|
|
<0.01
|
0.03
|
N0
|
201
|
26843
|
15340
|
27044
|
|
|
N1
|
53
|
5106
|
3572
|
8731
|
|
|
N2
|
114
|
18742
|
11325
|
30181
|
|
|
N3
|
32
|
7783
|
3400
|
11215
|
|
|
AJCC 7th Stage
|
|
|
|
|
<0.01
|
<0.01
|
I
|
66
|
15693
|
8382
|
24141
|
|
|
II
|
82
|
5123
|
4930
|
10135
|
|
|
III
|
91
|
10373
|
10214
|
20678
|
|
|
IV
|
161
|
27285
|
10111
|
37557
|
|
|
Surgery
|
|
|
|
|
<0.01
|
<0.01
|
Yes
|
197
|
19846
|
10149
|
30192
|
|
|
No
|
203
|
38628
|
23488
|
62319
|
|
|
Radiation
|
|
|
|
|
0.12
|
<0.01
|
Yes
|
151
|
24307
|
16911
|
41369
|
|
|
No/Unknown
|
249
|
34167
|
16726
|
51142
|
|
|
Chemotherapy
|
|
|
|
|
0.39
|
0.06
|
Yes
|
208
|
29142
|
15914
|
45264
|
|
|
No/Unknown
|
192
|
29332
|
17723
|
47247
|
|
|
Abbreviations: PSC = Pulmonary sarcomatoid carcinoma; LADC = Lung adenocarcinoma; LSCC = Lung squamous cell carcinoma.P-value*: Comparison between PSC with LADC. P-value**: Comparison between PSC to LSCC.
Survival
The OS for patients with PSC, LADC and LSCC can be illustrated by Kaplan-Meier plots (Fig. 2). PSC patients exhibited a worse OS than the other patient groups (P <0.001, Fig. 3, Table 4). The survival analyses also showed that older patients had much poorer survival than younger patients (p=0.0045, Fig. 5A). In addition, the OS of PSC patients with an advanced T stage was significantly shorter than that of PSC patients with a low T stage (p < 0.0001, Fig. 5B). Moreover, these patients had a better prognosis according to the earlier 7thedition of the AJCC guidelines (p < 0.0001, Fig. 5C). Patients who underwent surgery had better OS than those who did not (p < 0.0001, Fig. 6A). Similar to surgery, the prognosis of patients receiving radiation was much better than that of patients without radiation (p=0.014, Fig. 6B).
Table 4. Survival probabilities of each stage in PSC,LADC and LSCC.
Stage
|
OS
|
1-Year
|
3-Year
|
5-Year
|
Median
|
95%CI
|
All
|
PSC
|
42%
|
27%
|
21%
|
9
|
7.23-10.77
|
|
LADC
|
60%
|
37%
|
27%
|
20
|
9.63-20.37
|
|
LSCC
|
54%
|
30%
|
21%
|
15
|
14.69-15.31
|
Stage I
|
PSC
|
80%
|
61%
|
40%
|
58
|
41.67-74.33
|
|
LADC
|
91%
|
75%
|
62%
|
-
|
-
|
|
LSCC
|
83%
|
58%
|
44%
|
50
|
47.76-52.24
|
Stage II
|
PSC
|
60%
|
41%
|
30%
|
15
|
1.42-28.58
|
|
LADC
|
81%
|
56%
|
43%
|
47
|
44.01-45.00
|
|
LSCC
|
68%
|
41%
|
31%
|
25
|
23.58-26.42
|
Stage III
|
PSC
|
48%
|
28%
|
26%
|
12
|
8.70-15.30
|
|
LADC
|
67%
|
36%
|
23%
|
23
|
22.26-23.74
|
|
LSCC
|
53%
|
24%
|
16%
|
14
|
13.58-14.42
|
Stage IV
|
PSC
|
15%
|
6%
|
6%
|
3
|
2.11-3.89
|
|
LADC
|
36%
|
12%
|
6%
|
8
|
7.84-8.16
|
|
LSCC
|
25%
|
6%
|
3%
|
5
|
4.83-5.17
|
Abbreviations: PSC = Pulmonary sarcomatoid carcinoma; LADC = Lung adenocarcinoma; LSCC = Lung squamous cell carcinoma.
In the SEER cohort, the median survival times from diagnosis were 9, 20 and 15 months for PSC, LADC and LSCC patients, respectively, and 58 months for PSC patients with stage I disease, 15 months for patients with stage II disease, 12 months for patients with stage III disease and 3 months for patients with stage IV disease. All patients in stage IV had a poor prognosis. Since more than half of stage I LADC patients are still alive after the end of follow-up, the median survival time was not reached.
Features influencing prognosis
Univariate and multivariate Cox regression models identified the clinicopathological factors that were independently correlated with prognosis in OS for patients with PSC, namely, age at diagnosis (P<0.01), T stage (P<0.01), disease stage according to the 7th edition of the AJCC guidelines (P<0.01), surgery (P<0.01) and radiation (P<0.01, Table 3). Moreover, the multivariate analysis showed that patients aged 70 years or older had a worse OS than patients younger than 50 years (HR: 2.07, 95% CI: 1.23–3.50). Advanced T stage and advanced disease stage according to the 7th edition of the AJCC guidelines were risk factors for PSC patients. Patients who both underwent surgery and received radiation had a better prognosis than those who did not (HR: 2.29, 95% CI: 1.64–3.20, p < 0.01; HR: 1.43, 95% CI: 1.10–1.86, p < 0.01).
Table 3. Univariate and multivariate Cox regression analysis of prognostic factors in overall PSC patient cohort.
Characteristics
|
Univariate analysis Multivariate analysis
|
HR
|
95%CI
|
P-value
|
HR
|
95%CI
|
P-value
|
Age
|
|
|
<0.01
|
|
|
<0.01
|
<50
|
Ref.
|
|
|
Ref.
|
|
|
50-69
|
1.09
|
0.68-1.77
|
0.72
|
1.35
|
0.81-2.27
|
0.25
|
≥70
|
1.56
|
0.97-2.52
|
0.07
|
2.07
|
1.23-3.50
|
0.01
|
Sex
|
|
|
|
NA
|
|
|
Male
|
Ref.
|
|
|
|
|
|
Female
|
0.85
|
0.67-1.07
|
0.17
|
|
|
|
Race
|
|
|
0.23
|
NA
|
|
|
White
|
Ref.
|
|
|
|
|
|
Black
|
1.29
|
0.95-1.75
|
0.10
|
|
|
|
Others
|
0.95
|
0.59-1.51
|
0.81
|
|
|
|
Primary Site
|
|
|
0.08
|
NA
|
|
|
Main bronchus
|
Ref.
|
|
|
|
|
|
Upper lobe
|
0.53
|
0.27-1.03
|
0.06
|
|
|
|
Middle lobe
|
0.54
|
0.23-1.29
|
0.16
|
|
|
|
Lower lobe
|
0.61
|
0.31-1.23
|
0.17
|
|
|
|
Others
|
0.89
|
0.41-1.94
|
0.77
|
|
|
|
T stage
|
|
|
<0.01
|
|
|
<0.01
|
T0
|
Ref.
|
|
|
Ref.
|
|
|
T1
|
0.71
|
0.10-5.32
|
0.74
|
1.14
|
0.15-8.76
|
0.90
|
T2
|
1.67
|
0.23-12.01
|
0.61
|
2.81
|
0.38-20.77
|
0.31
|
T3
|
2.64
|
0.37-19.00
|
0.33
|
3.98
|
0.54-29.09
|
0.17
|
T4
|
3.32
|
0.46-23.85
|
0.23
|
3.81
|
0.52-27-87
|
0.19
|
N stage
|
|
|
<0.01
|
|
|
0.87
|
N0
|
Ref.
|
|
|
Ref.
|
|
|
N1
|
1.35
|
0.95-1.92
|
0.10
|
0.89
|
0.60-1.30
|
0.53
|
N2
|
1.83
|
1.41-2.38
|
<0.01
|
0.89
|
0.63-1.26
|
0.51
|
N3
|
1.80
|
1.17-2.77
|
<0.01
|
0.41
|
0.51-1.38
|
0.50
|
AJCC 7th Stage
|
|
|
<0.01
|
|
|
<0.01
|
I
|
Ref.
|
|
|
Ref.
|
|
|
II
|
1.71
|
1.08-2.70
|
0.02
|
0.98
|
0.59-1.64
|
0.95
|
III
|
2.25
|
1.46-3.49
|
<0.01
|
1.42
|
0.79-2.55
|
0.25
|
IV
|
5.67
|
3.78-8.51
|
<0.01
|
2.29
|
1.64-3.20
|
<0.01
|
Surgery
|
|
|
|
|
|
|
Yes
|
Ref.
|
|
|
Ref.
|
|
|
No
|
3.28
|
2.57-4.19
|
<0.01
|
2.29
|
1.64-3.20
|
<0.01
|
Radiation
|
|
|
|
|
|
|
Yes
|
Ref.
|
|
|
Ref.
|
|
|
No/Unknown
|
0.76
|
0.60-0.95
|
0.02
|
1.43
|
1.10-1.86
|
<0.01
|
Chemotherapy
|
|
|
|
NA
|
|
|
Yes
|
Ref.
|
|
|
|
|
|
No/Unknown
|
1.22
|
0.97-1.53
|
0.09
|
|
|
|
Abbreviations: CI, confidence interval; HR, hazard ratio; PSC = Pulmonary sarcomatoid carcinoma; LADC = Lung adenocarcinoma; LSCC = Lung squamous cell carcinoma.
*LCNEC = large-cell neuroendocrine carcinoma Ref. = Reference NA = not available
Difference in metastatic patterns among the three histological types
The common metastatic sites of PSCs were bone (12.8%), lung (12.3%), brain (10.8%) and liver (3.8%) (Table 2, Fig. 4). Among the patients with metastatic disease, PSC patients had significantly fewer bone (P<0.01), liver (P<0.01) and brain (P=0.03) metastases than LADC patients. In addition, LSCC patients had different metastatic patterns than patients with PSC, who had significantly more bone (P=0.02) and brain (P<0.01) metastases.
Table 2. Frequencies of each metastasis in PSC,LADC and LSCC.
|
PSC
n = 400 (%)
|
LADC
n = 58474 (%)
|
LSCC
n = 33637 (%)
|
P*
|
P**
|
Bone metastasis
|
|
|
|
<0.01
|
0.02
|
Yes
|
51(12.8)
|
11533(19.7)
|
3149(9.4)
|
|
|
No
|
349(87.3)
|
46941(80.3)
|
30488(90.6)
|
|
|
Brain metastasis
|
|
|
|
0.03
|
<0.01
|
Yes
|
43(10.8)
|
8600(14.7)
|
1661(4.9)
|
|
|
No
|
357(89.3)
|
49874(85.3)
|
31976(95.1)
|
|
|
Liver metastasis
|
|
|
|
<0.01
|
0.26
|
Yes
|
15(3.8)
|
4278(7.3)
|
1675(5.0)
|
|
|
No
|
385(95.3)
|
54196(92.7)
|
31962(95.0)
|
|
|
Lung metastasis
|
|
|
|
0.09
|
0.07
|
Yes
|
49(12.3)
|
8957(15.3)
|
3230(9.6)
|
|
|
No
|
351(87.8)
|
49517(84.7)
|
30407(90.4)
|
|
|
Abbreviations: PSC = Pulmonary sarcomatoid carcinoma; LADC = Lung adenocarcinoma; LSCC = Lung squamous cell carcinoma.P-value*: Comparison between PSC with LADC. P-value**: Comparison between PSC to LSCC.
Development of the nomogram and risk stratification model
Based on the selected significant parameters via the Cox regression model, a prognostic nomogram was established for OS (Fig. 7). The nomogram showed that T stage contributed the most to prognosis (T4: score 100; T3: score 96; T2: score 72, T1: score 3), followed by disease stage based on the 7th edition of the AJCC guidelines (IV: score 75, III: score 22, II: score 5), surgery (no surgery: score 68), age (≥70: score 55; 50–69: score 25), and radiation (no/unknown radiation: score 32). After summing the scores associated with each variable and projecting the total scores to the bottom scores, a patient’s probability of individual survival can easily be calculated at each time point. Furthermore, a risk stratification system was established based on each patient’s total scores from the nomogram to stratify all patients into three risk subgroups: low-risk group (total score<200), intermediate-risk group (total score 200-249), and high-risk group (total score ≥ 250). In addition, the median survival times of the low-, intermediate- and high-risk groups were 38.0, 6.0 and 4.0 months, respectively, and Kaplan-Meier methods indicated that the risk stratification model could differentiate survival outcomes among the three groups (P<0.0001, Fig. 10).
Validation and clinical performance of the nomogram
For PSC patients, the C-index of the nomogram in the validation set was 0.759 (95% CI 0.738–0.786). To confirm that the nomogram could effectively predict the prognosis of PSC patients, time-dependent ROC analyses at 1, 3 and 5 years were conducted. The 1-, 3-, and 5-year AUC values of the nomogram for the prediction of OS were 0.827, 0.826, and 0.8(Fig. 8A-C), respectively. Both the C-indexes and AUC values suggested that these models made accurate predictions and had good discriminative abilities. The calibration curves for the probability of 1-, 3- and 5-year OS demonstrated good consistency between the nomogram prediction and actual survival in the training cohort (Fig. 8D-F).
The DCA results of the nomogram demonstrated the good clinical applicability of the nomogram in terms of 1-, 3-, and 5-year patient survival (Fig. 9A). Based on the above, we further plotted the clinical impact curve to evaluate the clinical impact of the nomogram to help us more intuitively realize its significance. The nomogram for predicting OS demonstrated that cost/benefit ratios were lower than those when the risk threshold was less than 0.3 (Fig. 9B).