Patient characteristics
A total of 152 patients were selected from the SEER database according to the above criteria. Patients' demographic and clinical information was detailed in table 1. Most of the patients were diagnosed between 2013 and 2016. Patients, diagnosed with MAC at the median age of 56 years, were divided into two groups, which were younger than or equal to 55 years and older than 55 years. In all, 74 patients (48.7%) were ≤ 55 years and 78 (51.3%) were > 55 years. In addition, the disease had a slight predominance in women (Female:92, 60.5% vs Male:60, 39.5%), consistent with previous reports[4, 13, 14]. 122 patients (80.3%) of white race accounted for the majority, and more patients were married than unmarried (53.3% vs 44.1%). Regarding the literality, tumors occurred more common on the left (55.9%) than on the right (40.1%), which was contrary to the previous report that there were slightly more on the right than on the left[3]. In terms of tumor histology, the number of patients identified as grade I + II, grade III and grade IV were 6 (3.9%), 15(9.9%) and 4 (2.6%), respectively. For more than half of patients (127, 83.6%), their tumors' grade was unknown. In total, there were 54 (35.5%) patients with tumor size ≤ 10 cm, 83 (54.6%) patients with tumor size > 10 cm, and 15 patients with tumor size unknown. According to the AJCC 7th edition, the number of MAC patients with T4 (35.5%) was the highest, followed by T2 (23.0%), T3 (16.5%), and T1 (3.3%). There were more patients with N0 (67.8%) than patients with N1(22.3%).
Table 1
Characteristics of 152 MAC patients identified from SEER database between 2010 and 2016
Characteristic
|
No (%)
|
Patients
|
152
|
Year of diagnosis
|
|
2010–2012
|
60(39.5)
|
2013–2016
|
92(60.5)
|
Gender
|
|
Male
|
60(39.5)
|
Female
|
92(60.5)
|
Age at diagnosis(years)
|
|
≤55
|
74(48.7)
|
>55
|
78(51.3)
|
mean
|
53.7
|
Median
|
56
|
Race
|
|
White
|
122(80.3)
|
Black
|
15(9.8)
|
Others
|
12(7.9)
|
Unknown
|
3(2.0)
|
Marital status
|
|
Married
|
81(53.3)
|
unmarried
|
67(44.1)
|
unknown
|
4(2.6)
|
Laterality
|
|
Left
|
85(55.9)
|
Right
|
61(40.1)
|
Unknown
|
6(4.0)
|
Grade
|
|
I + II
|
6(3.9)
|
III
|
15(9.9)
|
IV
|
4(2.6)
|
Unknown
|
127(83.6)
|
Size
|
|
≤10 cm
|
54(35.5)
|
>10 cm
|
83(54.6)
|
Unknown
|
15(9.9)
|
T stage
|
|
T1
|
5(3.3)
|
T2
|
35(23.0)
|
T3
|
25(16.5)
|
T4
|
54(35.5)
|
Unknown
|
33(21.7)
|
N stage
|
|
N0
|
103(67.8)
|
N1
|
34(22.3)
|
Unknown
|
15(9.9)
|
Metastatic sites at diagnosis
|
|
Lung
|
|
Yes
|
100(65.8)
|
No
|
52(34.2)
|
Liver
|
|
Yes
|
91(59.9)
|
No
|
61(40.1)
|
Bone
|
|
Yes
|
31(20.4)
|
No
|
121(79.6)
|
Distant lymph node
|
|
Yes
|
34(22.4)
|
No
|
118(77.6)
|
Brain
|
|
Yes
|
1(0.7)
|
No
|
151(99.3)
|
Number of metastatic sites
|
|
1
|
77(50.7)
|
≥ 2
|
75(49.3)
|
Treatment
|
|
Surgery
|
|
Yes
|
59(38.8)
|
No
|
93(61.2)
|
Chemotherapy
|
|
Yes
|
101(66.4)
|
No/Unknown
|
51(33.6)
|
Radiotherapy
|
|
Yes
|
12(7.9)
|
No
|
140(92.1)
|
Vital status
|
|
Alive
|
41(27.0)
|
Dead
|
111(73.0)
|
1-year OS rate
|
29.0%
|
5-year OS rate
|
1.3%
|
With regard to the metastatic sites, 100 patients (65.8%) were diagnosed with metastases in lung, 91 (59.9%) in liver, 34 (22.4%) in distant lymph node, and 31 (20.4%) in bone. Except that, only one patient was diagnosed with brain metastases. In line with previous findings, liver and lung were considered as the most common metastatic sites[4, 15, 16]. There were quantitative differences from previous reports that the incidence of bone metastases was higher in our study[4, 13]. Moreover, we also summarized the metastatic patterns of single or multiple organs (Table 2). There were 77 patients (50.7%) with only one metastatic site, while more than one metastatic site was found in 75 patients (49.3%), lung and liver all accounting for a thumping majority for whether single or multiple metastases.
Table 2
Patterns of distant metastases for the 152 MAC patients
Sites of distant metastases
|
N (%)
|
One site of distant metastasis
|
77(50.7)
|
Lung
|
40(26.3)
|
Liver
|
26(17.1)
|
Bone
|
6(4.0)
|
Distant lymph node
|
4(2.6)
|
Brain
|
1(0.7)
|
Two sites of distant metastasis
|
49(32.2)
|
Liver + lung
|
29(19.1)
|
Bone + liver
|
8(5.3)
|
Liver + Distant lymph node
|
4(2.6)
|
Lung + Distant lymph node
|
4(2.6)
|
Bone + Lung
|
2(1.3)
|
Bone + Distant lymph node
|
2(1.3)
|
Three sites of distant metastasis
|
22(14.5)
|
Liver + lung + Distant lymph node
|
13(8.5)
|
Bone + liver + lung
|
6(4.0)
|
Bone + lung + Distant lymph node
|
2(1.3)
|
Bone + liver + Distant lymph node
|
1(0.7)
|
Four sites of distant metastasis
|
4(2.6)
|
Liver + lung + bone + Distant lymph node
|
4(2.6)
|
In general, 59 patients (38.8%) underwent surgery, among whom 32 patients (21.0%) received chemotherapy, 11 patients (7.2%) received chemotherapy and radiotherapy and 1 patient (0.7%) received radiotherapy; the remaining 15 patients (9.9%) didn't receive chemotherapy and radiotherapy or whether they had received chemotherapy was unknown. The specific surgical information of the patients was shown in Table 3, and it's unknown of the other 10 patients what kind of surgery they received. Besides, 58 patients (38.2%) only received chemotherapy, while 35 patients (23.0%) neither underwent surgery or radiotherapy nor accepted chemotherapy. A total of 111 (73.0%) deaths were recorded, and the 1- and 5-year OS rates for all the MAC patients were 29.0 and 1.3%, respectively.
Table 3
surgery information for the 49 patients
Primary site of surgery
|
Distant metastatic Site of surgery
|
Yes(N)
|
No(N)
|
Partial surgical removal
|
2
|
2
|
Total surgical removal
|
10
|
18
|
Debulking
|
0
|
2
|
Radical surgery a
|
6
|
9
|
a. Partial or total removal of the primary site with a resection in continuity (partial or total removal) with other organs.
Univariate and multivariate analysis of variables associated with OS in MAC patients
The median survival time for MAC patients was 7.0 ± 0.9 months (95% CI, 5.176 ~ 8.824). Then we used log-rank test for univariate analysis(Table 4), and the results showed that multiple factors,including diagnosed at the year between 2010 and 2012, unmarried, liver metastasis and patients with more than one metastatic site, were significantly associated with poor OS. On the contrary, surgery, chemotherapy and radiotherapy all could bring a survival benefit to patients. The other variables: patients’ age, gender, race, tumor size, grade and laterality, T stage, N stage and other metastatic sites except liver, didn't show statistically association with survival.
Table 4
Median survival data (months) and Kaplan–Meier method performs univariate analysis of variables in MAC patients
Variable
|
OS
|
Estimate ± SE
|
95%CI
|
log-rank P-value
|
Year of diagnosis
|
|
|
|
2010–2012
|
6.0 ± 1.0
|
4.112 ~ 7.888
|
0.045
|
2013–2016
|
8.0 ± 1.9
|
4.213 ~ 11.787
|
|
Age at diagnosis (years)
|
|
|
|
≤ 55
|
9.0 ± 2.5
|
4.058 ~ 13.942
|
0.128
|
>55
|
6.0 ± 1.2
|
3.607 ~ 8.393
|
|
Gender
|
|
|
|
Female
|
6.0 ± 1.2
|
3.693 ~ 8.307
|
0.840
|
Male
|
7.0 ± 1.7
|
3.666 ~ 10.335
|
|
Race
|
|
|
|
White
|
7.0 ± 1.0
|
5.137 ~ 8.863
|
0.690
|
Black
|
10.0 ± 3.9
|
2.371 ~ 17.629
|
|
Other
|
15.0 ± 6.0
|
3.215 ~ 26.785
|
|
Marital status
|
|
|
|
Married
|
8.0 ± 1.3
|
5.429 ~ 10.571
|
0.022
|
unmarried
|
5.0 ± 1.1
|
2.762 ~ 7.238
|
|
Grade
|
|
|
|
I + II
|
39.0 ± 31.0
|
0 ~ 99.760
|
0.161
|
III + IV
|
6.0 ± 1.0
|
4.111 ~ 7.889
|
|
Laterality
|
|
|
|
Left
|
7.0 ± 1.2
|
4.713 ~ 9.287
|
0.903
|
Right
|
8.0 ± 1.5
|
5.142 ~ 10.858
|
|
Size (cm)
|
|
|
|
≤ 10
|
6.0 ± 1.1
|
3.852 ~ 8.148
|
0.315
|
> 10
|
8.0 ± 1.9
|
4.286 ~ 11.714
|
|
T stage
|
|
|
|
T1-T2
|
7.0 ± 2.9
|
1.413 ~ 12.587
|
0.808
|
T3-T4
|
8.0 ± 1.6
|
4.940 ~ 11.060
|
|
N stage
|
|
|
|
N1
|
3.0 ± 0.7
|
1.637 ~ 4.363
|
0.122
|
N0
|
8.0 ± 1.4
|
5.724 ~ 10.726
|
|
Metastatic sites at diagnosis
|
|
|
|
Lung
|
|
|
|
Yes
|
6.0 ± 1.9
|
2.210 ~ 9.790
|
0.901
|
No
|
7.0 ± 0.9
|
5.152 ~ 8.848
|
|
Liver
|
|
|
|
Yes
|
6.0 ± 0.8
|
4.392 ~ 7.608
|
< 0.001
|
No
|
17.0 ± 5.4
|
6.483 ~ 27.517
|
|
Bone
|
|
|
|
Yes
|
7.0 ± 1.2
|
4.665 ~ 9.335
|
0.731
|
No
|
6.0 ± 1.3
|
3.363 ~ 8.637
|
|
Distant lymph node
|
|
|
|
Yes
|
2.0 ± 0.8
|
0.488 ~ 3.512
|
0.169
|
No
|
8.0 ± 1.3
|
5.490 ~ 10.510
|
|
No. of metastatic sites
|
|
|
|
1
|
10.0 ± 2.8
|
4.486 ~ 15.514
|
0.005
|
≥ 2
|
5.0 ± 1.0
|
3.024 ~ 6.976
|
|
Treatment
|
|
|
|
Surgery treatment
|
|
|
|
Yes
|
18.0 ± 2.7
|
12.752 ~ 23.248
|
< 0.001
|
No
|
4.0 ± 0.9
|
2.225 ~ 5.775
|
|
Chemotherapy
|
|
|
|
Yes
|
10.0 ± 2.2
|
5.781 ~ 14.219
|
< 0.001
|
No
|
3.0 ± 0.7
|
1.623 ~ 4.377
|
|
Radiation therapy
|
|
|
|
Yes
|
36.0 ± 18.0
|
3.864 ~ 8.136
|
0.017
|
No
|
6.0 ± 1.1
|
0.740 ~ 71.260
|
|
Overall
|
7.0 ± 0.9
|
5.176 ~ 8.824
|
|
Multivariate cox analysis was performed to further assess the potential factors which proved to be significant above. As shown in Table 5, year of diagnosis between 2013 and 2016, without liver metastasis, surgery and chemotherapy significantly predicted a better survival outcome. However, marital status, the number of distant metastatic organs and radiotherapy were not significantly bound up with the survival prognosis.
Table 5
Cox proportional hazards model performs multivariate analysis for OS in MAC patients
Variable
|
OS
|
HR (95%CI)
|
P value
|
Year of diagnosis
|
|
|
2010–2012
|
Reference
|
0.015
|
2013–2016
|
0.619(0.420 ~ 0.912)
|
|
Marital status
|
|
|
unmarried
|
Reference
|
0.091
|
Married
|
0.715(0.484 ~ 1.055)
|
|
Liver metastasis
|
|
|
No
|
Reference
|
0.014
|
Yes
|
1.818(1.130 ~ 2.926)
|
|
No. of metastatic sites
|
|
|
1
|
Reference
|
0.881
|
≥ 2
|
1.307(0.646 ~ 1.663)
|
|
Treatment
|
|
|
Surgery treatment
|
|
|
No
|
Reference
|
< 0.001
|
Yes
|
0.421(0.266 ~ 0.667)
|
|
Radiation therapy
|
|
|
No
|
Reference
|
0.421
|
Yes
|
0.674(0.257 ~ 1.764)
|
|
Chemotherapy
|
|
|
No
|
Reference
|
< 0.001
|
Yes
|
0.481(0.320 ~ 0.723)
|
|
Prognostic factors for patients with one or more metastatic sites
Furthermore, we conducted a separate prognostic analysis of patients with one or more distant metastases. The median survival time for MAC patients with one and more metastatic sites was 10.0 ± 2.8 and 5.0 ± 1.0 months, respectively (p = 0.005;Table 4 and Fig. 1A). Patients’ demographic and clinical information was listed in Table 6. Here, we focused on the patients with only liver or lung metastases, due to the insufficient numbers of patients with only bone, brain or distant lymph node metastases. For patients with one metastatic site (n = 66), the univariate Cox analysis turned out that the metastatic site and surgery were significantly associated with overall survival (Table 7). Multivariate Cox proportional hazard model analysis further proved the results that Compared with liver metastases, lung metastases had a better survival outcome (HR, 0.535; 95% CI, 0.297 ~ 0.964; p = 0.037), and the median survival time was 8 and 20 months for patients with liver and lung metastases, respectively (p = 0.023; Fig. 1B). Besides, compared with patients who didn’t received surgery, patients who underwent surgery were correlated with longer overall survival (HR, 0.372; 95% CI, 0.189 ~ 0.732; p = 0.004). For patients with more than one metastatic site (n = 75), marital status, treatments including surgery and chemotherapy were independent prognostic factors resulting from univariate Cox analysis (Table 7). Moreover, we included these variables in a multivariate Cox analysis and the results revealed that surgery and chemotherapy predicted better overall survival (Table 8). Then survival analysis was performed, and the results were showed in Fig. 2. For patients with distant metastases, whether one or more sites, surgery was significantly associated with improved survival months (1 site: surgery vs no-surgery: 21.0 vs 6.0 for median OS, Fig. 2A; >1 site: surgery vs no-surgery: 13.0 vs 4.0 for median OS, Fig. 2B) (all p < 0.05). However, the survival outcome of chemotherapy for the two groups showed different results. That is, the median OS for patients with more than one organ metastases were improved from 2 months to 9 months after receiving chemotherapy (Fig. 2C), while for patients with single organ metastasis, chemotherapy did not provide a statistically significant survival benefit. In addition, as the only statistically significant demographic variable, the median survival time of married patients was longer than that of unmarried patients from 4 months to 8 months (Fig. 2D).
Table 6
Characteristics of patients with one or more metastases
Characteristic
|
One metastatic site
|
More than one metastatic site
|
No (%)
|
No (%)
|
Patients
|
66
|
75
|
Year of diagnosis
|
|
|
2010–2012
|
27(40.9)
|
31(41.3)
|
2013–2016
|
39(59.1)
|
44(58.7)
|
Gender
|
|
|
Male
|
19(28.8)
|
36(48)
|
Female
|
47(71.2)
|
39(52)
|
Age at diagnosis(years)
|
|
|
≤55
|
32(48.5)
|
38(50.7)
|
>55
|
34(51.5)
|
37(49.3)
|
Race
|
|
|
White
|
55(83.3)
|
59(78.7)
|
Black
|
6(9.1)
|
9(12)
|
Others
|
5(7.6)
|
4(5.3)
|
Unknown
|
0
|
3(4)
|
Marital status
|
|
|
Married
|
37(56.1)
|
38(50.7)
|
unmarried
|
26(39.4)
|
36(48)
|
unknown
|
3(4.5)
|
1(1.3)
|
Laterality
|
|
|
Left
|
35(53.0)
|
45(60)
|
Right
|
29(44.0)
|
26(34.7)
|
Unknown
|
2(3.0)
|
4(5.3)
|
Grade
|
|
|
I + II
|
2(3.0)
|
3(4.0)
|
III + IV
|
5(7.6)
|
11(14.7)
|
Unknown
|
59(89.4)
|
61(81.3)
|
Size
|
|
|
≤10 cm
|
22(33.3)
|
24(32)
|
>10 cm
|
42(63.7)
|
38(50.7)
|
Unknown
|
2(3.0)
|
13(17.3)
|
T stage
|
|
|
T1
|
2(3.0)
|
2(2.7)
|
T2
|
14(21.2)
|
19(25.3)
|
T3
|
13(19.7)
|
8(10.7)
|
T4
|
26(39.4)
|
26(34.7)
|
Unknown
|
11(16.7)
|
20(26.7)
|
N stage
|
|
|
N0
|
51(77.3)
|
46(61.3)
|
N1
|
9(13.6)
|
22(29.3)
|
Unknown
|
6(9.1)
|
7(9.4)
|
Metastatic sites at diagnosis
|
|
|
Liver
|
26(39.4)
|
-
|
Lung
|
40(60.6)
|
-
|
Treatment
|
|
|
Surgery
|
|
|
Yes
|
34(51.5)
|
20(26.7)
|
No
|
32(48.5)
|
55(73.3)
|
Chemotherapy
|
|
|
Yes
|
45(68.2)
|
48(64)
|
No/Unknown
|
21(31.8)
|
27(36)
|
Radiotherapy
|
|
|
Yes
|
4(6.1)
|
6(8)
|
No
|
62(93.9)
|
69(92)
|
Vital status
|
|
|
Alive
|
20(30.3)
|
15(20)
|
Dead
|
46(69.7)
|
60(80)
|
1-year OS rate
|
36.4%
|
21.3%
|
5-year OS rate
|
3%
|
0%
|
Table 7
Univariate Cox regression analysis of prognostic factors in MAC patients with one or more metastases.
Variable
|
One site of distant metastases
|
More than one metastasis
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
Year of diagnosis
|
|
|
|
|
2010–2012
|
Reference
|
|
Reference
|
|
2013–2016
|
0.757(0.423 ~ 1.354)
|
0.348
|
0.776(0.465 ~ 1,293)
|
0.330
|
Age at diagnosis (years)
|
|
|
|
|
≤ 55
|
Reference
|
|
Reference
|
|
>55
|
1.295(0.719 ~ 2.331)
|
0.389
|
1.349(0.806 ~ 2.256)
|
0.254
|
Gender
|
|
|
|
|
Female
|
Reference
|
|
Reference
|
|
Male
|
0.761(0.398 ~ 1.457)
|
0.410
|
0.867(0.519 ~ 1.451)
|
0.588
|
Race
|
|
|
|
|
White
|
Reference
|
|
Reference
|
|
Black
|
0.449(0.108 ~ 1.864)
|
0.270
|
1.420(0.601 ~ 3.356)
|
0.424
|
Other
|
0.823(0.292 ~ 2.319)
|
0.712
|
0.603(0.145 ~ 2.504)
|
0.486
|
Marital status
|
|
|
|
|
unmarried
|
Reference
|
|
Reference
|
|
Married
|
0.737(0.397 ~ 1.368)
|
0.333
|
0.522(0.308 ~ 0.884)
|
0.016
|
Grade
|
|
|
|
|
I + II
|
Reference
|
|
Reference
|
|
III + IV
|
2.356(0.222 ~ 24.989)
|
0.477
|
5.347(0.664 ~ 43.044)
|
0.115
|
Laterality
|
|
|
|
|
Left
|
Reference
|
|
Reference
|
|
Right
|
1.462(0.801 ~ 2.667)
|
0.216
|
0.740(0.414 ~ 1.324)
|
0.310
|
Size (cm)
|
|
|
|
|
≤ 10
|
Reference
|
|
Reference
|
|
> 10
|
0.713(0.367 ~ 1.385)
|
0.318
|
0.788(0.445 ~ 1.395)
|
0.414
|
T stage
|
|
|
|
|
T1-T2
|
Reference
|
|
Reference
|
|
T3-T4
|
1.104(0.520 ~ 2.344)
|
0.797
|
0.821(0.442 ~ 1.527)
|
0.534
|
N stage
|
|
|
|
|
N0
|
Reference
|
|
Reference
|
|
N1
|
2.149(0.942 ~ 4.904)
|
0.069
|
1.001(0.551 ~ 1.820)
|
0.997
|
Metastatic sites
|
|
|
|
|
Liver
|
Reference
|
|
-
|
|
Lung
|
0.504(0.280 ~ 0.909)
|
0.023
|
-
|
-
|
Treatment
|
|
|
|
|
Surgery treatment
|
|
|
|
|
No
|
Reference
|
|
Reference
|
|
Yes
|
0.365(0.198 ~ 0.675)
|
0.001
|
0.425(0.224 ~ 0.805)
|
0.009
|
Radiation therapy
|
|
|
|
|
No
|
Reference
|
|
Reference
|
|
Yes
|
0.740(0.229 ~ 2.393)
|
0.615
|
0.280(0.068 ~ 1.148)
|
0.077
|
Chemotherapy
|
|
|
|
|
No
|
Reference
|
|
Reference
|
|
Yes
|
0.633(0.343 ~ 1.166)
|
0.142
|
0.333(0.195 ~ 0.571)
|
< 0.001
|
Table 8
Multivariate Cox regression analysis of prognostic factors for MAC patients with one or more metastases.
Variable
|
One site of distant metastasis
|
More than one metastasis
|
HR (95%CI)
|
P value
|
HR (95%CI)
|
P value
|
Marital status
|
|
|
|
|
unmarried
|
-
|
|
Reference
|
|
Married
|
-
|
-
|
0.573(0.334 ~ 0.985)
|
0.044
|
Metastatic sites
|
|
|
|
|
Liver
|
Reference
|
|
-
|
|
Lung
|
0.535(0.297 ~ 0.964)
|
0.037
|
-
|
-
|
Treatment
|
|
|
|
|
Surgery treatment
|
|
|
|
|
No
|
Reference
|
|
Reference
|
|
Yes
|
0.384(0.209 ~ 0.705)
|
0.002
|
0.372(0.189 ~ 0.732)
|
0.004
|
Chemotherapy
|
|
|
|
|
No
|
-
|
|
Reference
|
|
Yes
|
-
|
-
|
0.363(0.209 ~ 0.632)
|
< 0.001
|