UI and UI/U-Cr level in different clinicopathologic status among PTC patients
Among the 359 patients diagnosed with PTC, UI was not significantly different between different age, sex or other clinicopathological features, except that UI was significantly higher in CLNM(+) patients than in N0 patients (152 µg/L vs 126 µg/L, p = 0.028). After correction with creatinine, female and patients aged ≥ 45 exhibited significantly higher UI/U-Cr. Except variant subtypes (p = 0.021), no other pathological features were significantly different regarding UI/U-Cr level. Of note, capsular invasion tended to correlate with lower UI, but the difference was not statistically significant (p = 0.066) (Table 1).
Table 1
Comparisons of UI and UI/U-Cr between different clinicopathological status of PTC patients
Variables | n | UI, µg/L | P value | UI/Cr, µg/g | P value |
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Age | | | | | |
≥ 45 | 155 | 131 (87–198) | 0.266 | 97 (75–138) | 0 |
༜45 | 204 | 146.5 (97–210) | | 80 (56–124) | |
Sex | | | | | |
Male | 104 | 146 (103–201) | 0.353 | 76 (51–111) | 0 |
Female | 255 | 140 (86–208) | | 95 (70–142) | |
BMI, kg/㎡ | | | | | |
≥ 24 | 205 | 132 (90–197) | 0.261 | 86 (62–124) | 0.202 |
༜24 | 154 | 152 (96–218) | | 93 (67–137) | |
Tobacco use | | | | | |
Yes | 38 | 136 (94–218) | 0.782 | 86 (54–123) | 0.15 |
No | 321 | 140.0 (87–196) | | 91 (64–132) | |
Tumor size | | | | | |
≥ 1cm | 125 | 139 (86–197) | 0.711 | 95 (61–132) | 0.602 |
༜1cm | 234 | 142 (94–209) | | 87 (63–127) | |
Multifocality | | | | | |
Yes | 131 | 148 (96–208) | 0.53 | 95 (68–136) | 0.137 |
No | 228 | 136 (90–205) | | 86 (61–124) | |
Capsular invasion | | | | | |
Yes | 253 | 139 (84–195) | 0.066 | 90 (61–131) | 0.65 |
No | 106 | 148 (104–219) | | 90 (64–127) | |
Pathological subtype | | | | | |
Classic variant | 261 | 142 (94–209) | 0.484 | 86 (61–131) | 0.021 |
Follicular variant | 65 | 126(77–197) | | 90 (62–124) | |
Classic and follicular variant | 33 | 166 (87–215) | | 102 (85–143) | |
CLNM | | | | | |
Yes | 166 | 152 (105–215) | 0.028 | 94 (61–141) | 0.523 |
No | 193 | 126 (84–197) | | 90 (64–123) | |
Correlations of UI, UI/U-Cr and clinicopathological features of PTC patients
Using the median value as the cutoff, the patients were classified into an iodine-high and an iodine-low group to compare the difference of clinical and histopathological features. There were no significant difference in age, sex, BMI, smoking status, tumor size, multifocality, capsular invasion as well as variant subtypes in the two groups. In addition, iodine was not associated with coexisted nodular goiter, chronic thyroiditis or thyroid adenoma. However, patients in the UI-high group were more likely to be positive for CLNM compared with the UI-low group (p = 0.017) (Table 2).
Table.2 Association of UI and clinicopathological features of PTC |
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Variables | Urinary iodine, µg/L |
n (%) | Low (%) | High (%) | P value |
n = 181 | n = 178 |
Age | | | | |
≥ 45 | 155 (43.2) | 82 (22.8) | 73 (20.3) | 0.273 |
༜45 | 204 (56.8) | 96 (26.7) | 108 (30.1) | |
Sex | | | | |
Male | 104 (29) | 48 (13.4) | 56 (15.6) | 0.407 |
Female | 255 (71) | 130 (36.2) | 125 (34.8) | |
BMI, kg/㎡ | | | | |
≥ 24 | 205 (57.1) | 109 (30.4) | 96 (26.7) | 0.117 |
༜24 | 154 (42.9) | 69 (19.2) | 85 (23.7) | |
Diabetes | | | | |
Yes | 16 (4.5) | 9 (2.5) | 7 (1.9) | 0.585 |
No | 343 (95.5) | 169 (47.1) | 174 (48.5) | |
Hypertension | | | | |
Yes | 63 (17.5) | 37 (10.3) | 26 (7.2) | 0.11 |
No | 296 (82.5) | 141 (39.3) | 155 (43.2) | |
Tobacco use | | | | |
Yes | 38 (10.6) | 19 (5.3) | 19 (5.3) | 0.957 |
No | 321 (89.4) | 159 (44.3) | 162 (45.1) | |
Tumor size | | | | |
≥ 1cm | 125 (34.8) | 64 (17.8) | 61 (17) | 0.654 |
༜1cm | 234 (65.2) | 114 (31.8) | 120 (33.4) | |
Multifocality | | | | |
Yes | 131 (36.5) | 60 (16.7) | 71 (19.8) | 0.277 |
No | 228 (63.5) | 118 (32.9) | 110 (30.6) | |
Capsular invasion | | | | |
Yes | 253 (70.5) | 129 (35.9) | 124 (34.5) | 0.41 |
No | 106 (29.5) | 49 (13.6) | 57 (15.9) | |
Nodular goiter | | | | |
Yes | 99 (27.6) | 52 (14.5) | 47 (13.1) | 0.491 |
No | 260 (72.4) | 126 (35.1) | 134 (37.3) | |
Chronic thyroiditis | | | | |
Yes | 94 (26.2) | 50 (13.9) | 44 (12.3) | 0.415 |
No | 265 (73.8) | 128 (35.7) | 137 (38.2) | |
Thyroid adenoma | | | | |
Yes | 5 (1.4) | 3 (0.8) | 2 (0.6) | 0.683 |
No | 354 (98.6) | 175 (48.7) | 179 (49.9) | |
Variant subtype | | | | |
Classic | 261 (72.7) | 127 (35.4) | 134 (37.3) | 0.173 |
Follicular | 65 (18.1) | 38 (10.6) | 27 (7.5) | |
Classic and follicular (multiple foci) | 33 (9.2) | 13 (3.6) | 20 (5.6) | |
CLNM | | | | |
Yes | 166 (46.2) | 71 (19.8) | 95 (26.5) | 0.017 |
No | 193 (53.8) | 107 (29.8) | 86 (24) | |
As is shown in Table 3, female or patients aged ≥ 45 showed significantly higher UI/U-Cr (p < 0.001 and p < 0.01), which was due to the physiologically lower U-Cr among women and elders (Table 1). To reduce the imbalance of baseline data between the two groups (Table 3), a 1:1 PSM was performed to adjust for age and sex. After PSM, 118 age- and sex- adjusted patients in each of the two groups were identified, with no statistically differences in baseline characteristics. However, no significant differences were found in histopathlogical features and the distribution of CLNM (p = 0.295) (Table 3).
Table.3 Correlation of UI/U-Cr and clinicopathological features of PTC |
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| Before PSM | After PSM |
Variables | | UI/U-Cr, µg/g | | | UI/U-Cr, µg/g | |
n | Low | High | P value | n | Low | High | P value |
n = 176 | n = 183 | n = 118 | n = 118 |
Age | | | | | | | | |
≥ 45 | 155 (43.2) | 60 (16.7) | 95 (26.5) | 0.001 | 105 (44.5) | 49 (20.8) | 56 (23.7) | 0.359 |
༜45 | 204 (56.8) | 116 (32.3) | 88 (24.5) | | 131 (55.5) | 69 (29.2) | 62 (26.3) | |
Sex | | | | | | | | |
Male | 104 (29) | 63 (17.5) | 41 (11.4) | 0.005 | 59 (25) | 27 (11.4) | 32 (13.6) | 0.452 |
Female | 255 (71) | 113 (31.5) | 142 (39.6) | | 177 (75) | 91 (38.6) | 86 (36.4) | |
BMI, kg/㎡ | | | | | | | | |
≥ 24 | 205 (57.1) | 105 (29.2) | 100 (27.9) | 0.337 | 130 (55.1) | 67 (28.4) | 63 (26.7) | 0.601 |
༜24 | 154 (42.9) | 71 (19.8) | 83 (23.1) | | 106 (44.9) | 51 (21.6) | 55 (23.3) | |
Diabetes | | | | | | | | |
Yes | 16 (4.5) | 3 (0.8) | 13 (3.6) | 0.013 | 10 (4.2) | 2 (0.8) | 8 (3.4) | 0.102 |
No | 343 (95.5) | 173 (48.2) | 170 (47.4) | | 226 (95.8) | 116 (49.2) | 110 (46.6) | |
Hypertension | | | | | | | | |
Yes | 63 (17.5) | 29 (8.1) | 34 (9.5) | 0.601 | 41 (17.4) | 19 (8.1) | 22 (9.3) | 0.606 |
No | 296 (82.5) | 147 (40.9) | 149 (41.5) | | 195 (82.6) | 99 (41.9) | 96 (40.7) | |
Tobacco use | | | | | | | | |
Yes | 38 (10.6) | 21 (5.8) | 17 (4.7) | 0.416 | 25 (10.6) | 12 (5.1) | 13 (5.5) | 0.832 |
No | 321 (89.4) | 155 (43.2) | 166 (46.2) | | 211 (89.4) | 106 (44.9) | 105 (44.5) | |
Tumor size | | | | | | | | |
≥ 1cm | 125 (34.8) | 55 (15.3) | 70 (19.5) | 0.164 | 88 (37.3) | 40 (16.9) | 48 (20.3) | 0.282 |
< 1cm | 234 (65.2) | 121 (33.7) | 113 (31.5) | | 148 (62.7) | 78 (33.1) | 70 (29.7) | |
Multifocality | | | | | | | | |
Yes | 131 (36.5) | 57 (15.9) | 74 (20.6) | 0.113 | 93 (39.4) | 43 (18.2) | 50 (21.2) | 0.351 |
No | 228 (63.5) | 119 (33.1) | 109 (30.4) | | 143 (60.6) | 75 (31.8) | 68 (28.8) | |
Capsular invasion | | | | | | | | |
Yes | 253 (70.5) | 123 (34.3) | 130 (36.2) | 0.811 | 162 (68.6) | 83 (35.2) | 79 (33.5) | 0.575 |
No | 106 (29.5) | 53 (14.8) | 53 (14.8) | | 74 (31.4) | 35 (14.8) | 39 (16.5) | |
Nodular goiter | | | | | | | | |
Yes | 99 (27.6) | 50 (13.9) | 49 (13.6) | 0.729 | 66 (28) | 34 (14.4) | 32 (13.6) | 0.772 |
No | 260 (72.4) | 126 (35.1) | 134 (37.3) | | 170 (72) | 84 (35.6) | 86 (36.4) | |
Chronic thyroiditis | | | | | | | | |
Yes | 94 (26.2) | 40 (11.1) | 54 (15) | 0.144 | 63 (26.7) | 28 (11.9) | 35 (14.8) | 0.303 |
No | 265 (73.8) | 136 (37.9) | 129 (35.9) | | 173 (73.3) | 90 (38.1) | 83 (35.2) | |
Thyroid adenoma | | | | | | | | |
Yes | 5 (1.4) | 4 (1.1) | 1 (0.3) | 0.207 | 3 (1.3) | 2 (0.8) | 1 (0.4) | 1 |
No | 354 (98.6) | 172 (47.9) | 182 (50.7) | | 233 (98.7) | 116 (49.2) | 117 (49.6) | |
Variant subtype | | | | | | | | |
Classic | 261 (72.7) | 136 (37.9) | 125 (34.8) | 0.054 | 164 (69.5) | 84 (35.6) | 80 (33.9) | 0.432 |
Follicular | 65 (18.1) | 30 (8.4) | 35 (9.7) | | 48 (20.3) | 25 (10.6) | 23 (9.7) | |
Classic and follicular (multiple foci) | 33 (9.2) | 10 (2.8) | 23 (6.4) | | 24 (10.2) | 9 (3.8) | 15 (6.4) | |
CLNM | | | | | | | | |
Yes | 166 (46.2) | 80 (22.3) | 86 (24) | 0.77 | 106 (44.9) | 49 (20.8) | 57 (24.2) | 0.295 |
No | 193 (53.8) | 96 (26.7) | 97 (27) | | 130 (55.1) | 69 (29.2) | 61 (25.8) | |
Risk factors of central lymph node metastasis in PTC patients
According to the results above, CLNM was closely related to a higher level of UI. However, CLNM is a pathological process affected by multiple risk factors, which could be potential confounders in the relationship of urinary iodine level and lymph node metastasis. To better understand the relationship of UI and CLNM, we further explored the risk factors that may contribute to the presence of CLNM. As Table 4 shows, age was significantly lower in patients with CLNM (p < 0.001). Tumor size was significantly larger in patients with CLNM (p < 0.001). The classic variant of PTC was more likely to present with CLNM than the follicular variant (p < 0.001). Furthermore, CLNM was marginally correlated with multiple foci (p = 0.064) (Table 4).
Table 4
Risk factors of central lymph node metastasis for PTC patients
Variables | CLNM | |
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Yes | No | P value |
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Age | | | |
≥ 45 | 53 | 102 | 0 |
༜45 | 113 | 91 | |
Sex | | | |
Male | 53 | 51 | 0.252 |
Female | 113 | 142 | |
BMI, kg/㎡ | | | |
≥ 24 | 92 | 113 | 0.551 |
< 24 | 74 | 80 | |
Tumor size | | | |
≥ 1cm | 74 | 51 | 0 |
< 1cm | 92 | 142 | |
Multifocality | | | |
Yes | 69 | 62 | 0.064 |
No | 97 | 131 | |
Capsular invasion | | | |
Yes | 120 | 133 | 0.484 |
No | 46 | 60 | |
Nodular goiter | | | |
Yes | 41 | 58 | 0.258 |
No | 125 | 135 | |
Chronic thyroiditis | | | |
Yes | 46 | 48 | 0.542 |
No | 120 | 145 | |
Thyroid adenoma | | | |
Yes | 3 | 2 | 0.666 |
No | 163 | 191 | |
Variant subtype | | | |
Classic | 135 | 126 | 0 |
Follicular | 15 | 50 | |
Classic and follicular (multiple foci) | 16 | 17 | |
Univariate and multivariate logistic regression analyses on the urinary iodine level for the presence of CLMN in PTC patients
First, we investigated the association of age, tumor size, multifocality, variant subtype and the presence of CLNM by univariate logistic regression analysis. In total PTC patients, age, tumor size and classic variant were significantly associated with CLNM with an OR of 0.96 (95% CI: 0.94–0.98), 2.01 (95% CI: 1.31–3.14) and 3.57 (95% CI: 1.95–6.88). Meanwhile, multifocality was marginally related to positive CLNM (OR: 1.50, 95% CI: 0.98–2.32) .
Based on the WHO criteria, we found that insufficient iodine (≤ 99 µg/L) tended to be inversely associated with CLNM by univariate regression analysis (Table 5). However, no significant associations were found after adjusted for age, sex, multifocality, tumor size and variant subtype. After we defined insufficient iodine as ≤ 109 µg/L and above requirements as ≥ 190 µg/L, we found that low UI was a protective factor for CLNM by univariate analysis (OR: 0.44, 95% CI: 0.26–0.72) and remained an independent protective factor in multivariate analysis (OR: 0.53, 95% CI: 0.31–0.91). In subgroup analysis, lower iodine was also correlated with N0 both in PTC ≥ 1cm and PTC < 1cm by univariate analysis. And multivariate analysis revealed that low UI remained an independent protective factor for CLNM in PTC < 1cm (OR: 0.43, 95% CI: 0.21–0.87) (Table 5).
Table.5 Univariate and Multivariate Logistic Regression Analysis on UI Level for the Presence of CLNM in PTC patients |
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| Univariate | Multivariate c |
Urinary iodine status | OR | 95% CI | P value | OR | 95% CI | P value |
(µg/L) |
Total patientsa | | | | | | |
≤ 99 (n = 102) | 0.59 | 0.36–0.98 | 0.043 | 0.71 | 0.41–1.23 | 0.221 |
100–199 (n = 164) | reference | | | reference | | |
≥ 200 (n = 93) | 0.98 | 0.59–1.63 | 0.934 | 0.99 | 0.59–1.83 | 0.98 |
PTC ≥ 1cma | | | | | | |
≤ 99 (n = 39) | 0.4 | 0.17–0.91 | 0.031 | 0.51 | 0.20–1.30 | 0.161 |
100–199 (n = 56) | reference | | | reference | | |
≥ 200 (n = 30) | 1.03 | 0.41–2.69 | 0.956 | 1.26 | 0.44–3.73 | 0.674 |
PTC < 1cma | | | | | | |
≤ 99 (n = 63) | 0.7 | 0.36–1.33 | 0.281 | 0.73 | 0.35–1.48 | 0.381 |
100–199 (n = 108) | reference | | | reference | | |
≥ 200 (n = 63) | 0.98 | 0.52–1.85 | 0.96 | 1.09 | 0.55–2.15 | 0.815 |
Total patientsb | | | | | | |
≤ 109 (n = 135) | 0.44 | 0.26–0.72 | 0.001 | 0.53 | 0.31–0.91 | 0.021 |
110–189 (n = 120) | reference | | | reference | | |
≥ 190 (n = 104) | 0.68 | 0.40–1.15 | 0.154 | 0.71 | 0.41–1.29 | 0.281 |
PTC ≥ 1cmb | | | | | | |
≤ 109 (n = 50) | 0.38 | 0.16–0.89 | 0.028 | 0.59 | 0.22–1.58 | 0.294 |
110–189 (n = 42) | reference | | | reference | | |
≥ 190 (n = 33) | 0.9 | 0.34–2.40 | 0.826 | 1.33 | 0.45–4.06 | 0.608 |
PTC < 1cmb | | | | | | |
≤ 109 (n = 85) | 0.44 | 0.23–0.83 | 0.012 | 0.43 | 0.21–0.87 | 0.019 |
110–189 (n = 78) | reference | | | reference | | |
≥ 190 (n = 71) | 0.61 | 0.32–1.18 | 0.143 | 0.65 | 0.32–1.33 | 0.242 |
a. Iodine insufficient, adequate and above requirements (including excessive) were defined as: ≤99 µg/L, 100–199 µg/L and ≥ 200 µg/L |
b. Iodine insufficient, adequate and above requirements (including excessive) were defined as: ≤109 µg/L, 110–189 µg/L and ≥ 190 µg/L |
c. Adjusted for age, sex, multifocality, tumor size and variant subtype |