Patient characteristics of the surgical specimens of OSCC
A total of 674 patients were included in this study; 488 patients were excluded, and 186 who met the criteria were subjected to further analyses. The clinicopathological characteristics of 186 patients with OSCC, including 92 with early and 94 with progressive OSCC, are shown in Supplementary Table 1 (Additional File 1). Among the 186 patients with OSCC, 123 (66%) had pDOI >5 mm, and 85 (46%) had pDOI >10 mm. Fifty-eight (31%) had lymph node metastasis, and 16 and 42 patients were classified as having pN1 and pN2–3, respectively. ENE was detected in 27 (15%) of the 186 patients with OSCC. Overall, 93% (25 of 27) of patients with ENE were in the progressive stage. No high-risk HPV was detected in any patient (Additional Files 2 and 3).
Table 1
|
All patients
(n=186)
|
Early OSCC
(n=92)
|
Progressive OSCC
(n=94)
|
Characteristics
|
No. of
patients
|
%
|
No. of
patients
|
%
|
No. of
patients
|
%
|
Sex
|
Female
|
71
|
(38.1)
|
36
|
(39.1)
|
35
|
(37.2)
|
|
Male
|
115
|
(61.8)
|
56
|
(60.9)
|
59
|
(62.8)
|
Age, years
|
Mean age
|
68.9 (range, 31−91)
|
69 (range, 31−91)
|
68.6 (range, 38−87)
|
|
≥64
|
57
|
(30.6)
|
27
|
(29.3)
|
30
|
(31.9)
|
|
<64
|
129
|
(69.4)
|
65
|
(70.7)
|
64
|
(68.1)
|
High-risk HPV exposure
|
No
|
186
|
(100)
|
92
|
(100)
|
94
|
(100)
|
Anatomical site
|
Palate
|
4
|
(2.1)
|
4
|
(4.3)
|
0
|
(0)
|
|
Oral floor
|
3
|
(1.6)
|
2
|
(2.2)
|
1
|
(1.1)
|
|
Gingiva
|
29
|
(15.6)
|
4
|
(4.3)
|
25
|
(26.6)
|
|
Tongue
|
129
|
(69.3)
|
67
|
(72.8)
|
62
|
(66.0)
|
|
Buccal mucosa
|
21
|
(11.3)
|
15
|
(16.3)
|
6
|
(0)
|
DOI
|
≤5 mm
|
63
|
(33.9)
|
58
|
(63.0)
|
5
|
(5.3)
|
|
>5 mm
|
123
|
(66.1)
|
34
|
(40.0)
|
89
|
(94.7)
|
DOI
|
≤10 mm
|
102
|
(54.9)
|
92
|
(100)
|
10
|
(10.6)
|
|
>10 mm
|
84
|
(45.2)
|
0
|
(0)
|
84
|
(9.4)
|
LyV
|
Negative
|
73
|
(39.2)
|
54
|
(58.7)
|
19
|
(20.2)
|
|
Positive
|
113
|
(60.8)
|
38
|
(41.3)
|
75
|
(79.8)
|
ENE
|
Negative
|
159
|
(85.5)
|
90
|
(97.8)
|
69
|
(73.4)
|
|
Positive
|
27
|
(14.5)
|
2
|
(2.2)
|
25
|
(26.6)
|
pT
|
1, 2
|
92
|
(49.5)
|
92
|
(100)
|
0
|
(0)
|
|
3, 4
|
94
|
(50.5)
|
0
|
(0)
|
94
|
(100)
|
pN
|
0
|
128
|
(68.8)
|
83
|
(90.2)
|
45
|
(47.9)
|
|
1
|
16
|
(8.6)
|
4
|
(4.3)
|
12
|
(64.5)
|
|
2, 3
|
42
|
(22.6)
|
5
|
(5.4)
|
37
|
(19.9)
|
OSCC, oral squamous cell carcinoma; HPV, human papilloma virus; DOI, depth of invasion; LyV, lymphovascular invasion; ENE, extranodal extension; pT, pathological T; pN, pathological N. DOI included both cDOI and pDOI because the cohorts of clinical DOI and pathological DOI were matched 100% (concordance rate=100%); cutoff points were DOI ≤5 mm/DOI >5 mm and DOI ≤10 mm/DOI >10 mm. |
Association of the clinicopathological features with DR, TB, and TILs in the resected specimens
Table 2 shows the association of the clinicopathological features with DR, TB, and TILs in the resected specimens. DR-I, TB-H, and TILs-L were significantly associated with pDOI >10 mm (p<0.001, 0.01, and <0.001, respectively) and pT stage (1, 2 versus 3, 4) (p<0.001, 0.01, and <0.001, respectively). These three factors were also significantly associated with the presence of lymphovascular invasion and lymph node metastasis (all p<0.05). Moreover, infiltrative growth was significantly associated with DR-I, TB-H, and TILs-L (p<0.001, 0.01, and <0.01, respectively). However, tumor location was not significantly associated with DR, TB, or TILs.
Table 2
Association of clinicopathological features with DR, TB, and TILs using surgically resected specimens
|
Desmoplastic reaction
|
Tumor budding
|
Tumor-infiltrating lymphocytes
|
|
Mature
|
(%)
|
Immature
|
(%)
|
p-value
|
Low
|
(%)
|
High
|
(%)
|
p-value
|
High
|
(%)
|
Low
|
%
|
p-value
|
Sex
|
|
|
|
|
0.81
|
|
|
|
|
0.19
|
|
|
|
|
0.06
|
Female
|
29
|
(41)
|
42
|
(59)
|
|
53
|
(75)
|
18
|
(25)
|
|
44
|
(62)
|
27
|
(38)
|
|
Male
|
49
|
(43)
|
66
|
(57)
|
|
95
|
(83)
|
20
|
(17)
|
|
55
|
(48)
|
60
|
(52)
|
|
Age, years
|
|
|
|
|
0.17
|
|
|
|
|
<0.001
|
|
|
|
|
0.59
|
<65
|
28
|
(49)
|
29
|
(50)
|
|
41
|
(72)
|
16
|
(28)
|
|
32
|
(56)
|
25
|
(44)
|
|
≥65
|
50
|
(39)
|
79
|
(61)
|
|
107
|
(83)
|
22
|
(17)
|
|
67
|
(52)
|
62
|
(48)
|
|
Location
|
|
|
|
|
0.63
|
|
|
|
|
0.6
|
|
|
|
|
0.36
|
Palate
|
3
|
(75)
|
1
|
(21)
|
|
4
|
(100)
|
0
|
(0)
|
|
3
|
(75)
|
1
|
(25)
|
|
Oral floor
|
1
|
(33)
|
2
|
(60)
|
|
3
|
(100)
|
0
|
(0)
|
|
2
|
(67)
|
1
|
(33)
|
|
Gingiva
|
12
|
(41)
|
17
|
(58)
|
|
22
|
(76)
|
7
|
(24)
|
|
11
|
(38)
|
18
|
(62)
|
|
Tongue
|
55
|
(43)
|
74
|
(57)
|
|
101
|
(78)
|
28
|
(22)
|
|
70
|
(54)
|
59
|
(46)
|
|
Buccal mucosa
|
7
|
(33)
|
14
|
(66)
|
|
18
|
(86)
|
3
|
(14)
|
|
13
|
(62)
|
8
|
(38)
|
|
pDOI
|
|
|
|
|
<0.001
|
|
|
|
|
0.06
|
|
|
|
|
<0.001
|
≥5 mm
|
46
|
(73)
|
17
|
(27)
|
|
55
|
(87)
|
8
|
(13)
|
|
49
|
(78)
|
14
|
(22)
|
|
<5 mm
|
32
|
(26)
|
91
|
(74)
|
|
93
|
(76)
|
30
|
(24)
|
|
50
|
(41)
|
73
|
(59)
|
|
pDOI
|
|
|
|
|
<0.001
|
|
|
|
|
0.01
|
|
|
|
|
<0.001
|
≥10 mm
|
57
|
(56)
|
45
|
(44)
|
|
88
|
(86)
|
14
|
(14)
|
|
72
|
(71)
|
30
|
(29)
|
|
<10 mm
|
21
|
(25)
|
63
|
(75)
|
|
60
|
(71)
|
24
|
(29)
|
|
27
|
(32)
|
57
|
(68)
|
|
Metastasis
|
|
|
|
|
<0.001
|
|
|
|
|
0.02
|
|
|
|
|
<0.001
|
Absent
|
68
|
(53)
|
60
|
(47)
|
|
108
|
(84)
|
20
|
(16)
|
|
79
|
(62)
|
49
|
(38)
|
|
Present
|
10
|
(17)
|
48
|
(83)
|
|
40
|
(69)
|
18
|
(31)
|
|
20
|
(34)
|
38
|
(66)
|
|
Number of LNs
|
|
|
|
|
<0.001
|
|
|
|
|
0.03
|
|
|
|
|
<0.001
|
n=0
|
68
|
(53)
|
60
|
(47)
|
|
108
|
(84)
|
20
|
(16)
|
|
79
|
(62)
|
49
|
(38)
|
|
n=1
|
5
|
(23)
|
16
|
(76)
|
|
16
|
(76)
|
5
|
(24)
|
|
10
|
(48)
|
11
|
(52)
|
|
n>2
|
5
|
(13)
|
32
|
(86)
|
|
24
|
(65)
|
13
|
(35)
|
|
10
|
(27)
|
27
|
(73)
|
|
Pattern of invasion
|
|
|
|
|
<0.001
|
|
|
|
|
0.01
|
|
|
|
|
<0.01
|
1, 2
|
30
|
(70)
|
13
|
(30)
|
|
40
|
(93)
|
3
|
(7)
|
|
31
|
(72)
|
12
|
(28)
|
|
3, 4
|
48
|
(34)
|
95
|
(66)
|
|
108
|
(76)
|
35
|
(24)
|
|
68
|
(48)
|
75
|
(52)
|
|
LyV
|
|
|
|
|
<0.001
|
|
|
|
|
0.03
|
|
|
|
|
<0.001
|
Absent
|
44
|
(60)
|
29
|
(39)
|
|
64
|
(88)
|
9
|
(12)
|
|
50
|
(68)
|
23
|
(32)
|
|
Present
|
34
|
(30)
|
79
|
(70)
|
|
84
|
(74)
|
29
|
(26)
|
|
49
|
(43)
|
64
|
(57)
|
|
pT
|
|
|
|
|
<0.001
|
|
|
|
|
0.01
|
|
|
|
|
<0.001
|
1, 2
|
54
|
(59)
|
38
|
(41)
|
|
80
|
(87)
|
12
|
(13)
|
|
67
|
(73)
|
25
|
(27)
|
|
3. 4
|
24
|
(26)
|
70
|
(74)
|
|
68
|
(72)
|
26
|
(28)
|
|
32
|
(34)
|
62
|
(66)
|
|
pN
|
|
|
|
|
<0.001
|
|
|
|
|
0.02
|
|
|
|
|
<0.01
|
0
|
68
|
(53)
|
60
|
(47)
|
|
108
|
(84)
|
20
|
(16)
|
|
79
|
(42)
|
49
|
(41)
|
|
1,
|
3
|
(19)
|
13
|
(81)
|
|
13
|
(81)
|
3
|
(19)
|
|
6
|
(37)
|
10
|
(63)
|
|
2, 3
|
7
|
(17)
|
35
|
(83)
|
|
27
|
(64)
|
15
|
(36)
|
|
14
|
(33)
|
28
|
(67)
|
|
OSCC, oral squamous cell carcinoma; DR, desmoplastic reaction; TB, tumor budding; TILs, tumor-infiltrating lymphocytes; pDOI, pathological depth of invasion; LN, lymph nodes; LyV, lymphovascular invasion; pT, pathological T; pN, pathological N. |
Boldface indicates statistically significant values. |
Association among DR, TB, and TILs in the resected specimens and ENE
The results of the association among DR, TB, and TILs in the resected specimens and ENE sites are shown in Table 3. These three pathological features of the resection specimens were significantly associated with those of the ENE sites (all p<0.05).
Based on the clinicopathological analysis of DR, TB, and TILs in the resected specimens and association analysis with ENE, it was indicated that evaluating DR, TB, and TILs in the primary sites, as well as from ENE, could predict tumor behavior.
Table 3
Relationships among DR, TB, and TILs in ENE and resection (n=27).
|
|
In matched ENE (n=27)
|
In matched resection (n=27)
|
|
DR-M
|
DR-I
|
CR
|
p-value
|
DR-M
|
3
|
2
|
89%
|
<0.01
|
DR-I
|
1
|
21
|
|
TB-L
|
TB-H
|
CR
|
p-value
|
TB-L
|
13
|
2
|
74%
|
0.01
|
TB-H
|
5
|
7
|
|
TILs-H
|
TILs-L
|
CR
|
p-value
|
TILs-H
|
13
|
4
|
78%
|
<0.01
|
TILs-L
|
2
|
8
|
DR, desmoplastic reaction; TB, tumor budding; TILs, tumor-infiltrating lymphocytes; ENE, extranodal extension; CR, concordance rate; DR-I, immature desmoplastic reaction; DR-M, mature desmoplastic reaction; TB-H, high tumor budding; TB-L, low tumor budding; TILs-L, low-grade tumor-infiltrating lymphocytes; TILs-H, high-grade tumor-infiltrating lymphocyte |
Patient characteristics of the OSCC in matched biopsies
We subsequently examined whether biopsy-derived DR, TB, and TILs would be useful histopathological factors to predict tumor behavior. A total of 131 biopsies were collected from the matched patients, and 83 biopsies (51%, 83 of 186), including 36 from patients with early and 47 from those with progressive OSCC, met the criteria and were then subjected to further analyses (Additional File 4). Of the 83 biopsies, 27 (33%) had lymph nodes metastasis, and 10 patients with ENE were available (12%, 10/83), all of whom were in the progressive stage. cDOI was unavailable in three of 186 OSCC cases (SCC 103, SCC 152, and SCC 163); two had artifacts, and one was evaluated by computed tomography. Among the 183 cDOI evaluated cases, the concordance rate of DOI ≤5 mm and DOI >5 mm and of DOI≤10 mm and DOI>10 mm between cDOI and pDOI was 100% (Supplementary Table 1 in Additional File 1). However, the three unavailable cases were not included in the analysis of biopsy specimens; accordingly, cDOI was applicable in all 83 biopsies, 54 (66%) of which had cDOI >5 mm and 41 (48%) had cDOI ≤10 mm.
Association of the clinicopathological features with DR, TB, and TILs in biopsy specimens
Table 4 summarizes the association of clinicopathological features with DR, TB, and TILs in biopsy specimens. DR-I and TILs-L were significantly associated with cDOI >5 mm, cDOI >10 mm, and pT stage (all p<0.01) similar to that in resected specimens, although TB was not significantly associated. DR-I and TILs-L were also significantly associated with the presence and number of lymph node metastases (all p<0.05). TB-H was significantly associated with the number of metastatic lymph nodes (p=0.02). DR, TB, and TILs were not significantly associated with tumor location.
Table 4
Association of clinicopathological features with DR, TB, and TILs in biopsy specimens
|
Desmoplastic reaction
|
Budding
|
Tumor-infiltrating lymphocytes
|
|
Mature
|
(%)
|
Immature
|
(%)
|
p-value
|
Low
|
(%)
|
High
|
(%)
|
p-value
|
High
|
(%)
|
Low
|
%
|
p-value
|
Sex
|
|
|
|
|
0.44
|
|
|
|
|
0.62
|
|
|
|
|
0.5
|
Female
|
13
|
(39)
|
20
|
(61)
|
|
26
|
(79)
|
7
|
(21)
|
|
19
|
(58)
|
14
|
(42)
|
|
Male
|
24
|
(48)
|
26
|
(52)
|
|
37
|
(74)
|
13
|
(26)
|
|
25
|
(50)
|
25
|
(50)
|
|
Age, years
|
|
|
|
|
0.53
|
|
|
|
|
0.51
|
|
|
|
|
0.68
|
<63
|
12
|
(40)
|
18
|
60)
|
|
24
|
(80)
|
6
|
(20)
|
|
15
|
(50)
|
15
|
(50)
|
|
≥64
|
25
|
(47)
|
28
|
(53)
|
|
39
|
(74)
|
14
|
(26)
|
|
29
|
(55)
|
24
|
(45)
|
|
Location
|
|
|
|
|
0.7
|
|
|
|
|
0.6
|
|
|
|
|
0.73
|
Palate
|
1
|
(100)
|
0
|
(0)
|
|
1
|
(100)
|
0
|
(0)
|
|
1
|
(100)
|
0
|
(0)
|
|
Oral floor
|
0
|
(0)
|
0
|
(0)
|
|
0
|
(0)
|
0
|
(0)
|
|
0
|
(0)
|
0
|
(0)
|
|
Gingiva
|
6
|
(43)
|
8
|
(57)
|
|
12
|
(86)
|
2
|
(14)
|
|
7
|
(50)
|
7
|
(50)
|
|
Tongue
|
26
|
(43)
|
34
|
(57)
|
|
45
|
(75)
|
15
|
(25)
|
|
31
|
(52)
|
29
|
(48)
|
|
Buccal mucosa
|
4
|
(50)
|
4
|
(50)
|
|
5
|
(62)
|
3
|
(38)
|
|
5
|
(63)
|
3
|
(38)
|
|
cDOI
|
|
|
|
|
<0.001
|
|
|
|
|
0.28
|
|
|
|
|
<0.01
|
≤5 mm
|
25
|
(86)
|
4
|
(14)
|
|
24
|
(83)
|
5
|
(17)
|
|
22
|
(76)
|
7
|
(24)
|
|
>5 mm
|
12
|
(22)
|
42
|
(78)
|
|
39
|
(72)
|
15
|
(328)
|
|
22
|
(41)
|
32
|
(59)
|
|
cDOI
|
|
|
|
|
<0.001
|
|
|
|
|
0.1
|
|
|
|
|
<0.001
|
≤10 mm
|
29
|
(69)
|
13
|
(31)
|
|
35
|
(83)
|
7
|
(17)
|
|
31
|
(74)
|
11
|
(26)
|
|
>10 mm
|
8
|
(20)
|
33
|
(80)
|
|
28
|
(68)
|
13
|
(32)
|
|
13
|
(32)
|
28
|
(68)
|
|
Metastasis
|
|
|
|
|
<0.01
|
|
|
|
|
0.41
|
|
|
|
|
<0.01
|
Absent
|
31
|
(55)
|
25
|
(45)
|
|
44
|
(79)
|
12
|
(21)
|
|
36
|
(64)
|
20
|
(36)
|
|
Present
|
6
|
(22)
|
21
|
(78)
|
|
19
|
(70)
|
8
|
(30)
|
|
8
|
(30)
|
19
|
(70)
|
|
Number of LNs
|
|
|
|
|
0.02
|
|
|
|
|
0.049
|
|
|
|
|
0.01
|
n=0
|
31
|
(55)
|
25
|
(45)
|
|
44
|
(79)
|
12
|
(21)
|
|
36
|
(64)
|
20
|
(36)
|
|
n=1
|
2
|
(17)
|
10
|
(83)
|
|
11
|
(92)
|
1
|
(8)
|
|
3
|
(25)
|
9
|
(75)
|
|
n≧2
|
4
|
(27)
|
11
|
(73)
|
|
8
|
(53)
|
7
|
(47)
|
|
5
|
(33)
|
10
|
(67)
|
|
pT
|
|
|
|
|
<0.001
|
|
|
|
|
0.06
|
|
|
|
|
<0.001
|
1, 2
|
27
|
(75)
|
9
|
(25)
|
|
31
|
(86)
|
5
|
(14)
|
|
27
|
(75)
|
9
|
(25)
|
|
3, 4
|
10
|
(21)
|
37
|
(79)
|
|
32
|
(68)
|
15
|
(32)
|
|
17
|
(36)
|
30
|
(64)
|
|
pN
|
|
|
|
|
0.02
|
|
|
|
|
0.2
|
|
|
|
|
0.01
|
0
|
31
|
(55)
|
25
|
(45)
|
|
44
|
(79)
|
12
|
(21)
|
|
36
|
(64)
|
20
|
(36)
|
|
1
|
2
|
(22)
|
7
|
(78)
|
|
8
|
(89)
|
1
|
(11)
|
|
2
|
(22)
|
7
|
(78)
|
|
2, 3
|
4
|
(22)
|
14
|
(78)
|
|
11
|
(61)
|
7
|
(39)
|
|
6
|
(33)
|
12
|
(67)
|
|
DR, desmoplastic reaction; TB, tumor budding; TILs, tumor-infiltrating lymphocytes; cDOI, clinical depth of invasion; LN, lymph nodes; pT, pathological T; pN, pathological N. |
Association among DR, TB, and TILs in biopsies and ENE sites
Similar to resections, the three pathological features of biopsies were significantly associated with those of the ENE site (all p<0.05, Table 5). In addition, these three features in biopsies were also significantly associated with matched resections (all p≤0.001, Table 6).
Table 5
Relationships among DR, TB, and TILs in ENE and biopsy (n=10)
|
|
In matched ENE (n=10)
|
In matched biopsy (n=10)
|
|
DR-M
|
DR-I
|
CR
|
p-value
|
DR-M
|
0
|
0
|
100%
|
―
|
DR-I
|
0
|
10
|
|
TB-L
|
TB-H
|
CR
|
p-value
|
TB-L
|
5
|
1
|
90%
|
0.02
|
TB-H
|
0
|
4
|
|
TILs-H
|
TILs-L
|
CR
|
p-value
|
TILs-H
|
1
|
1
|
90%
|
0.03
|
TILs-L
|
0
|
8
|
DR, desmoplastic reaction; TB, tumor budding; TILs, tumor-infiltrating lymphocytes; ENE, extranodal extension; CR, concordance rate; DR-I, immature desmoplastic reaction; DR-M, mature desmoplastic reaction; TB-H, high tumor budding; TB-L, low tumor budding; TILs-L, low-grade tumor-infiltrating lymphocytes; TILs-H, high-grade tumor-infiltrating lymphocytes |
Table 6
Relationships among DR, TB, and TILs in biopsy and resection (n=83)
|
|
In matched biopsy (n=83)
|
In matched resection (n=83)
|
|
DR-M
|
DR-I
|
CR
|
p-value
|
DR-M
|
30
|
7
|
83%
|
<0.001
|
DR-I
|
7
|
39
|
|
TB-L
|
TB-H
|
CR
|
p-value
|
TB-L
|
55
|
11
|
77%
|
0.001
|
TB-H
|
8
|
9
|
|
TILs-H
|
TILs-L
|
CR
|
p-value
|
TILs-H
|
36
|
8
|
82%
|
<0.001
|
TILs-L
|
8
|
31
|
DR, desmoplastic reaction; TB, tumor budding; TILs, tumor-infiltrating lymphocytes; ENE, extranodal extension; CR, concordance rate; DR-I, immature desmoplastic reaction; DR-M, mature desmoplastic reaction; TB-H, high tumor budding; TB-L, low tumor budding; TILs-L, low-grade tumor-infiltrating lymphocytes; TILs-H, high-grade tumor-infiltrating lymphocytes |
Based on the results, similar to that in the resected specimens, histopathological evaluation of DR, TB, and TILs in a biopsy was proven to be useful for predicting the clinicopathological features and tumor behavior, including metastatic potential and invasiveness, at ENE in metastatic lymph nodes.
Predictive factors for the presence of ENE and the predictive value of single or combined risk factors for resected specimens
Evaluating the histological factors of DR, TB, and TILs in both biopsies and resections could predict tumor behavior, including lymph node metastasis activity and tumor behavior in ENE; therefore, we performed bivariate and multivariate analyses to evaluate the predictive factors for detecting ENE in resected specimens. To evaluate the predictive factors for ENE, we performed the analyses in all patients, those with progressive OSCC, and those with lymph node metastasis. The bivariate analysis showed that the independent variables for predicting ENE were TB-H (odds ratio [OR]=3.30, 95% confidence interval [CI]=1.15−9.60; p=0.03) and pDOI >10 mm (OR=6.90, 95% CI=1.49−31.9; p=0.01) in all patients; TB-H (OR=1.04, 95% CI=1.37−13.3; p=0.01) in those with progressive OSCC; and TB-H (OR=5.70, 95% CI=1.39−23.4; p=0.02) in those with lymph node metastasis (Table 7). However, the multivariate logistic regression revealed that TB-H (OR=3.14, 95% CI=1.25−7.91; p<0.001) and pDOI >10 mm (OR=8.05, 95% CI=2.62−24.7; p<0.001) were independent factors for ENE (Table 7). In the biopsies, bivariate logistic regression analyses revealed no significant relationships between the risk factors and presence of ENE (Additional File 5).
Table 7
Bivariate and multivariate logistic regression analyses of ENE using surgically resected specimens
|
Bivariate
|
Multivariate
|
|
Odds ratio
|
95% CI
|
p
|
Odds ratio
|
95% CI
|
p
|
All (n=186)
|
|
|
|
|
|
|
DR-I
|
1.71
|
0.52−5.63
|
0.38
|
|
|
|
TB-H
|
3.30
|
1.15−9.60
|
0.03
|
3.14
|
1.25−7.91
|
<0.001
|
TILs-L
|
1.74
|
0.59−5.12
|
0.31
|
|
|
|
pDOI >5 mm
|
1.47
|
0.18−11.7
|
0.71
|
|
|
|
pDOI >10 mm
|
6.90
|
1.49−31.9
|
0.01
|
8.05
|
2.62−24.7
|
<0.001
|
Progressive (n=94)
|
|
|
|
|
|
|
DR-I
|
1.04
|
0.29−3.68
|
0.94
|
|
|
|
TB-H
|
1.04
|
1.37−13.3
|
0.01
|
|
|
|
TILs-L
|
1.59
|
0.50−5.02
|
0.42
|
|
|
|
pDOI >5 mm
|
1.06
|
0.04−27.4
|
0.97
|
|
|
|
pDOI >10 mm
|
1.40
|
0.13−14.4
|
0.67
|
|
|
|
Metastasis (n=56)
|
|
|
|
|
|
|
DR-I
|
0.58
|
0.13-2.66
|
0.48
|
|
|
|
TB-H
|
5.70
|
1.39−23.4
|
0.02
|
|
|
|
TILs-L
|
2.37
|
0.64−9.94
|
0.20
|
|
|
|
pDOI >5 mm
|
0.31
|
0.02−4.40
|
0.38
|
|
|
|
pDOI >10 mm
|
2.99
|
0.50−17.9
|
0.23
|
|
|
|
CI, confidence interval; DR-I, immature desmoplastic reaction; TB-H, high tumor budding; TILs-L, low-grade tumor-infiltrating lymphocytes; pDOI, pathological depth of invasion; ENE, extranodal extension. |
Association between pathological high-risk factors and the presence of ENE
The sensitivity, specificity, PPV, NPV, and accuracy for single or a combination of independent factors for pathological features in detecting ENE were analyzed (Table 8). In the resected specimens, TB-H showed high specificity and low sensitivity for the presence of ENE (sensitivity, 44%; specificity, 84%; accuracy, 78%). In contrast, pDOI >10 mm exhibited high sensitivity and low specificity (sensitivity, 85%; specificity, 62%; accuracy, 65%). The combination of TB-H and pDOI >10 mm (TB-H/pDOI>10 mm) showed the highest specificity and accuracy (sensitivity, 37%; specificity, 91%; accuracy, 83%).
Table 8
Prediction of ENE by single and combination risk factors in biopsy and surgically resected specimens
Risk factors
|
Sensitivity (%)
|
Specificity (%)
|
PPV (%)
|
NPV (%)
|
Accuracy (%)
|
p
|
Cohort proportions
(n; yes vs. no)
|
Surgically resected specimens
|
|
|
|
|
|
|
|
TB-H
|
44
|
84
|
33
|
90
|
78
|
<0.01
|
(38:148)
|
pDOI >10 mm
|
85
|
62
|
27
|
96
|
65
|
<0.01
|
(84:102)
|
TB-H/pDOI >10 mm
|
37
|
91
|
42
|
88
|
83
|
<0.01
|
(24:162)
|
Biopsy specimens
|
|
DR-I
|
100
|
51
|
22
|
100
|
57
|
<0.01
|
(46:37)
|
TILs-L
|
80
|
58
|
21
|
95
|
60
|
0.03
|
(39:44)
|
TB-H
|
-
|
-
|
-
|
-
|
-
|
0.16
|
(20:63)
|
cDOI >10 mm
|
90
|
56
|
22
|
98
|
60
|
<0.01
|
(41:42)
|
DR-I/TILs-L
|
80
|
31
|
26
|
96
|
70
|
<0.01
|
(31:52)
|
DR-I/TILs-L/cDOI >10 mm
|
70
|
77
|
29
|
95
|
76
|
<0.01
|
(24:59)
|
PPV, positive predictive value; NPV, negative predictive value; CR, concordance rate; TB-H, high tumor budding; pDOI, pathological depth of invasion; DR-I, immature desmoplastic reaction; TILs-L, low-grade tumor-infiltrating lymphocytes; cDOI, clinical depth of invasion; ENE, extranodal extension. Boldface indicates statistically significant values. |
In the biopsy specimens, although no independent histological factors were noted for predicting ENE, significant associations between ENE and the status of DR-I, TILs-L, and radiologically evaluated cDOI >10 mm were detected (all p<0.05). The histological features of DR-I, TILs-L, and cDOI >10 mm exhibited high sensitivity but low specificity and low accuracy (all sensitivity, >80%; all specificity, <60%; all accuracy, <60%). The combination of DR-I and TILs-L (DR-I/TILs-L) also showed high sensitivity but low specificity and accuracy (80%, 31%, and 70%, respectively). The combination of DR-I, TILs-L, and cDOI >10 mm (DR-I/TILs-L/cDOI >10 mm) demonstrated >70% sensitivity, 77% specificity, and 76% accuracy.. Moreover, TB-H/pDOI>10 mm, DR-I/TILs-L, and DR-I/TILs-L/cDOI>10 mm could identify all ENEmi (100%, 5/5) (Additional File 6).