The correlation between preoperative serum thyroglobulin and pathological features of thyroid follicular carcinoma

doi:10.21203/rs.3.rs-1965404/v1

Purpose:

To explore more meaningful information for making individualized medical decisions for patients with follicular thyroid carcinoma (FTC), we investigated the correlations between pathological features of FTC and preoperative serum markers, including thyroglobulin (Tg), anti-thyroglobulin antibody (TgAb), thyroid peroxidase antibodies (TPOAb), thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and fT3/fT4 ratio.

Methods:

We retrospectively analyzed 82 patients with FTC. Data collected included demographics (sex and age), pathological features (infiltration extent, tumor stage, presence of multifocal FTC, and presence of concomitant PTC), and preoperative serum markers (Tg, TgAb, TPOAb, TSH, fT3, fT4, and fT3/fT4 ratio). The correlations between preoperative serum markers and pathological features were analyzed.

Results:

72.0% patients were female. Mean age was 46.4±16.5 years. In univariate analysis, older age (≥55 years) was associated with non-minimally invasive (P=0.016), larger (>T2 category, P=0.006), and multifocal (P=0.034) FTC; elevated preoperative serum Tg level (≥500.00 ng/mL) was associated with non-minimally invasive (P=0.015) and larger (>T2 category, P=0.001) FTC; higher fT3/fT4 ratio (≥0.541) was associated with multifocal FTC (P=0.031). In multivariable analysis, Tg ≥500.00 ng/mL was an independent risk factor for non-minimally invasive FTC [P=0.015, OR=3.289 (1.260-8.583)] and for >T2 category FTC [P=0.001, OR=5.397 (1.963-14.840)]; older age [≥55 years, P=0.045, OR=4.756 (1.037-21.818)] and higher fT3\fT4 ratio [≥0.541, P=0.044, OR=4.626 (1.043-20.525)] was an independent risk factor multifocal FTC, respectively.

Conclusions:

Preoperative serum Tg was correlated with the local tumor extent and primary tumor diameter of FTC. Further research regarding the utility of preoperative serum Tg in FTC is still needed.

Thyroid Neoplasm

Follicular

Thyroglobulin

Pathology

Preoperative

Follicular thyroid carcinoma (FTC) is the second most common differentiated thyroid cancer (DTC) and represents 10–15% of all malignant thyroid tumors [1]. It is known that FTC has a high propensity for hematogenous spread, and about 15–27% of these patients develop distant metastasis associated with a low survival rate [2]. Currently, the WHO classification of FTC and the American Joint Committee on Cancer (AJCC) staging system of DTC are mainly used to evaluate prognosis and provide personalized management recommendations for these patients based on postoperative pathology [2, 3].

To explore more meaningful preoperative data for making individualized medical decisions for patients with DTC, many previous studies have investigated the correlations between pathological stage of DTC and serum markers related to thyroid, focusing on, but not limited to, thyroglobulin (Tg), anti-thyroglobulin antibody (TgAb), thyroid peroxidase antibodies (TPOAb) and thyroid stimulating hormone (TSH) [4–7]. However, there are considerable differences in the incidence rates of various thyroid cancer subtypes [1]. Compared with papillary thyroid carcinoma (PTC), the most common subtype of DTC (more than 80% of all thyroid malignancy), clinical research evidence centering on the relationships between the pathological result of FTC and serum markers is insufficient.

Therefore, in this study, we tentatively investigated whether pathological features of FTC are correlated with preoperative serum Tg, TgAb, TPOAb, TSH, free triiodothyronine (fT3), free thyroxine (fT4), and fT3/fT4 ratio.

This retrospective study was approved by the Institutional Review Board, and the requirement for informed consent to review pathological results and other relevant medical records was waived off.

Patients

Patients who were diagnosed with FTC based on surgical pathology following thyroidectomy at our medical center between January 2014 and October 2021 were included in this study. Then, patients without the tests of preoperative serum Tg, TgAb, TPOAb, TSH, fT3, or fT4 within one month were excluded.

Pathological classifications

Based on postoperative pathological results, each neoplasm was categorized as minimally invasive follicular thyroid cancer (MI-FTC, diagnosed by capsular invasion alone), encapsulated angioinvasive follicular thyroid cancer (EA-FTC, diagnosed by capsular invasion with <4 vascular invasion), and widely invasive follicular thyroid cancer (WI-FTC, diagnosed by ≥4 vascular invasion or widespread infiltration of extrathyroidal tissue) according to the WHO classification of FTC [2].

In addition, all neoplasms were retrospectively evaluated using the AJCC staging system of DTC [3]. The extent of the tumor (T-category) and lymph node (N-category) were described based on thyroid surgery. The presence of metastasis (M-category) was defined by other preoperative medical records of the patients, including the determination of distant pathological biopsy or positive finding of ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT).

Patients with multifocal FTC or concomitant PTC were recorded as well.

Serum markers

The electrochemiluminescence immunoassay was used for the estimation of serum Tg (normal reference range: 3.50–77.00 ng/mL), TgAb (normal reference range: 0–115.00 IU/mL), and TPOAb levels (normal reference range: 0–34.00 IU/mL). TSH (normal reference range: 0.560–5.910 μIU/mL), fT3 (normal reference range: 3.53–7.37 pmol/L), and fT4 levels (normal reference range: 7.98–16.02 pmol/L) were determined using chemiluminescence immunoassay. fT3/fT4 ratio was calculated as fT3 (pmol/L)/fT4 (pmol/L). All serum markers were measured at our center.

For further analysis, all serum markers were divided into two groups by 3rd quartile, respectively.

Data and statistical analysis

Categorical variables were expressed as frequencies (percentage). Continuous variables of normal distribution were expressed as mean ± standard deviation (SD) and of abnormal distribution as median [interquartile range (IQR)]. Differences between pathological classifications for categorical variables were analyzed using Chi-squared test or Fisher’s exact test, as applicable. Continuous variables were assessed using Student’s t test or Mann–Whitney U test according to statistical needs.

Univariate and multivariate logistic regression analysis were performed to identify risk factors for different pathological features. The stepwise forward method was used to include significant factors in the multivariate logistic regression analysis.

All statistical analyses were performed using SPSS (version 23.0, IBM) software, and two-sided P values <0.05 were considered indicative of statistical significance.

A total of 82 patients with FTC were included in this study. These included 59 (72.0%) women and 23 (28.0%) men; the mean age of patients was 46.4 ± 16.5 years.

Baseline

The median maximum diameter of FTC was 3.0 (2.0-4.5) cm. According to the WHO classification of FTC [2], 52 (63.5%) patients had MI-FTC, 17 (20.7%) had EA-FTC, and 11 (13.4%) had WI-FTC. Based on the AJCC staging system of DTC [3], there were 24 (29.3%) patients with T1 category, 30 (36.6%) with T2 category, 23 (28.0%) with T3 category, and 3 (3.7%) with T4 category. The pathological classification and T-category of the 2 (2.4%) patients could not be classified due to the imperfect material. 9 (11.0%) patients were positive for lymph node invasion. Distant metastatic lesions were preoperatively found in 9 (11.0%) patients.

In terms of other pathological features, 73 (89.0%) patients were solitary FTC, and 9 (11.0%) were multiple; 10 (12.2%) patients with FTC were accompanied by PTC, and 72 (77.8%) were not.

The preoperative median level of Tg was 333.75 (39.99–500.00) ng/mL, of TgAb was 14.30 (10.00-67.35) IU/mL, and of TPOAb was 11.97 (7.83–25.49) IU/mL. Among the thyroid functional parameters, the preoperative median level of TSH was 1.305 (0.802–2.208) µIU/mL, of fT3 was 4.94 (4.51–5.50) pmol/L, of fT4 was 10.83 (9.44–11.90) pmol/L, and of fT3/fT4 ratio was 0.462 (0.410–0.541).

Other details of the baseline were shown in Table 1 and Table 2.

Table 1

Demographic and Pathological features of 82 FTCs
Variables	No.(%), mean ± SD or median (IQR)
Sex
Male	23(28.0)
Female	59(72.0)
Age (years)	46.4 ± 16.5
< 55	55(67.1)
≥ 55	27(32.9)
Pathological classification^a
Unclassifiable	2(2.4)
MI-FTC	52(63.5)
EA-FTC	17(20.7)
WI-FTC	11(13.4)
Maximum diameters (cm)^a	3.0(2.0-4.5)
T-category^a
Tx	2(2.4)
T1	24(29.3)
T2	30(36.6)
T3	23(28.0)
T4	3(3.7)
N-category
N0	73(89.0)
N1	9(11.0)
M-category
M0	73(89.0)
M1	9(11.0)
Lesion
Solitary	73(89.0)
Multifocal	9(11.0)
Concomitant PTC
NO	72(77.8)
YES	10(12.2)
a. The pathological classification, maximum diameter and T-category of the two patients could not be defined in the records due to the problem of surgical sampling.
Abbreviations: FTC, follicular thyroid carcinoma; MI-FTC, minimally invasive follicular thyroid cancer; EA-FTC, encapsulated angioinvasive follicular thyroid cancer; WI-FTC, widely invasive follicular thyroid cancer; PTC, papillary thyroid carcinoma.

Table 2

Serological characteristics and distributions of 82 FTCs
Variables	No.(%), median (IQR) or mean ± SD
Tg (ng/mL)	333.75(39.99–500.00)
< 77.00	26(31.7)
≥ 77.00	56(68.3)
TgAb (IU/mL)	14.30(10.00-67.35)
< 115.00	68(82.9)
≥ 115.00	14(17.1)
TPOAb (IU/mL)	11.97(7.83–25.49)
< 34.00	65(79.3)
≥ 34.00	17(20.7)
TSH (µIU/mL)	1.305(0.802–2.208)
fT3 (pmol/L)	4.94(4.51–5.50)
fT4 (pmol/L)	10.83(9.44–11.90)
fT3/fT4	0.462(0.410–0.541)
Abbreviations: Tg, thyroglobulin; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; fT3, free triiodothyronine; fT4, free thyroxine.

Differences between pathological features

There were significant differences between the proportion of patients with MI-FTC and non-MI-FTC (EA-FTC and WI-FTC) in the group of age (< 55 years and ≥ 55 years), and the group of Tg level (< 500.00 ng/mL and ≥ 500.00 ng/mL). The proportion of patients with non-MI-FTC (50.0%) was higher than MI-FTC (23.1%) in the older group of patients (≥ 55 years, P = 0.014). The patients with non-MI-FTC (57.1%) were more common than MI-FTC (28.8%) in the group with elevated Tg (≥ 500.00 ng/mL, P = 0.013). In other demographic and serological characteristics, no significant difference between MI-FTC and non-MI-FTC was found. There were no significant differences between WI-FTC and non-WI-FTC (MI-FTC and EA-FTC) in all characteristics.

Similarly, there were significant differences between the proportion of patients with ≤ T2 category and > T2 category FTC in the group of age (< 55 years and ≥ 55 years), and the group of Tg level (< 500.00 ng/mL and ≥ 500.00 ng/mL). The proportion of patients with > T2 category FTC (53.8%) was higher than ≤ T2 category (22.2%) in the older group of patients (≥ 55 years, P = 0.005). The patients with > T2 category FTC (65.4%) were more common than ≤ T2 category (25.9%) in the group with elevated Tg (≥ 500.00 ng/mL, P = 0.001). No significant difference between ≤ T2 category and > T2 category FTC was found in other variables. There were no significant differences in N-category, and M-category in all variables, respectively.

In addition, there were significant differences between the proportion of patients with solitary lesion and multifocal lesions in the group of age (< 55 years and ≥ 55 years), and the group of fT3/fT4 ratio (< 0.541 and ≥ 0.541). The proportion of patients with multifocal lesions (66.7%) was higher than solitary lesion (28.8%) in the older group of patients (≥ 55 years, P = 0.031). The patients with multifocal lesions (55.6%) were more common than solitary lesion (20.5%) in the group with elevated fT3/fT4 ratio (≥ 0.541, P = 0.035). No significant difference between the solitary lesion and multifocal lesions was found in other parameters. There were no significant differences between the FTC patients with concomitant PTC and without PTC in all parameters.

The detailed comparisons among different pathological features were shown in Supplementary 1, Supplementary 2, and Supplementary 3.

Indicators of pathological features

In univariate logistic regression analysis, the group of older age (≥ 55 years) and the group of elevated Tg level (≥ 500.00 ng/mL) were significant risk factors for non-MI-FTC (EA-FTC and WI-FTC) compared with the MI-FTC patients. In multivariate logistic regression analysis, the group of elevated Tg level [≥ 500.00 ng/mL, 3.289 (1.260–8.583), P = 0.015] was an independent risk factor for non-MI-FTC.

By comparison with the patients with ≤ T2 category FTC, the group of older age (≥ 55 years) and the group of elevated Tg level (≥ 500.00 ng/mL) were significant risk factors for > T2 category FTC using univariate logistic regression analysis. In multivariate logistic regression analysis, the group of elevated Tg level [≥ 500.00 ng/mL, 5.397 (1.963–14.840), P = 0.001] was an independent risk factor for > T2 category.

In univariate logistic regression analysis, the group of older age (≥ 55 years) and the group of elevated fT3/fT4 ratio (≥ 0.541) were significant risk factors for multifocal FTC in comparison with solitary FTC. In multivariate logistic regression analysis, the group of older age [≥ 55 years, 4.756 (1.037–21.818), P = 0.045] and the group of elevated fT3/fT4 ratio [≥ 0.541, 4.626 (1.043–20.525), P = 0.044] were independent risk factors for multifocal FTC.

The details of logistic regression analysis among different pathological features were shown in Table 3, Table 4, and Table 5.

Table 3

Logistic regression analysis on indicators of the pathological classification
		Pathological classification
				Univariate		Multivariate				Univariate		Multivariate
Variables		MI-FTC	EA-FTC + WI-FTC	P	OR (95% CI)	P	OR (95% CI)	MI-FTC + EA-FTC	WI-FTC	P	OR (95% CI)	P	OR (95% CI)
		(n = 52)	(n = 28)					(n = 69)	(n = 11)
Sex	Male	14(26.9)	7(25.0)	0.852	1.105 (0.386–3.166)	-	-	18(26.1)	3(27.3)	0.934	0.941 (0.225–3.939)	-	-
	Female	38(73.1)	21(75.0)	0.852	1.105 (0.386–3.166)	-	-	51(73.9)	8(72.7)	0.934	0.941 (0.225–3.939)	-	-
Age (years)	< 55	40(76.9)	14(50.0)	0.016	3.333 (1.248–8.902)	-	-	47(68.1)	7(63.6)	0.769	1.221 (0.323–4.610)	-	-
	≥ 55	12(23.1)	14(50.0)	0.016	3.333 (1.248–8.902)	-	-	22(31.9)	4(36.4)	0.769	1.221 (0.323–4.610)	-	-
Tg (ng/mL)	< 500.00	37(71.2)	12(42.9)	0.015	3.289 (1.260–8.583)	0.015	3.289 (1.260–8.583)	44(63.8)	5(45.5)	0.254	2.112 (0.585–7.629)	-	-
	≥ 500.00	15(28.8)	16(57.1)	0.015	3.289 (1.260–8.583)	0.015	3.289 (1.260–8.583)	25(36.2)	6(54.4)	0.254	2.112 (0.585–7.629)	-	-
TgAb (IU/mL)	< 67.35	39(75.0)	21(75.0)	1.000	1.000 (0.346–2.889)	-	-	54(78.3)	6(54.4)	0.102	3.000 (0.803–11.202)	-	-
	≥ 67.35	13(25.0)	7(25.0)	1.000	1.000 (0.346–2.889)	-	-	15(21.7)	5(45.5)	0.102	3.000 (0.803–11.202)	-	-
TPOAb (IU/mL)	< 25.49	37(71.2)	23(82.1)	0.283	0.536 (0.172–1.673)	-	-	53(76.8)	7(63.6)	0.354	1.893 (0.491–7.299)	-	-
	≥ 25.49	15(28.8)	5(17.9)	0.283	0.536 (0.172–1.673)	-	-	16(23.2)	4(36.4)	0.354	1.893 (0.491–7.299)	-	-
TSH (µIU/mL)	< 2.208	38(73.1)	23(82.1)	0.366	0.590 (0.188–1.854)	-	-	52(75.4)	9(81.8)	0.642	0.680 (0.134–3.459)	-	-
	≥ 2.208	14(26.9)	5(17.9)	0.366	0.590 (0.188–1.854)	-	-	17(24.6)	2(18.2)	0.642	0.680 (0.134–3.459)	-	-
fT3 (pmol/L)	< 5.50	38(73.1)	23(82.1)	0.366	0.590 (0.188–1.854)	-	-	52(75.4)	9(81.8)	0.642	0.680 (0.134–3.459)	-	-
	≥ 5.50	14(26.9)	5(17.9)	0.366	0.590 (0.188–1.854)	-	-	17(24.6)	2(18.2)	0.642	0.680 (0.134–3.459)	-	-
fT4 (pmol/L)	< 11.90	39(75.0)	22(78.6)	0.721	0.818 (0.272–2.457)	-	-	51(73.9)	10(90.9)	0.245	0.283 (0.034–2.372)	-	-
	≥ 11.90	13(25.0)	6(21.4)	0.721	0.818 (0.272–2.457)	-	-	18(26.1)	1(9.1)	0.245	0.283 (0.034–2.372)	-	-
fT3/fT4	< 0.541	40(76.9)	21(75.0)	0.847	1.111 (0.381–3.244)	-	-	54(78.3)	7(63.6)	0.297	2.057 (0.537–7.976)	-	-
	≥ 0.541	12(23.1)	7(25.0)	0.847	1.111 (0.381–3.244)	-	-	15(21.7)	4(36.4)	0.297	2.057 (0.537–7.976)	-	-
Abbreviations: MI-FTC, minimally invasive follicular thyroid cancer; EA-FTC, encapsulated angioinvasive follicular thyroid cancer; WI-FTC, widely invasive follicular thyroid cancer; Tg, thyroglobulin; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; fT3, free triiodothyronine; fT4, free thyroxine; OR, odds ratio; CI, confidence interval.

Table 4

Logistic regression analysis on indicators of the T-category, N-category and M-category
		T-category						N-category						M-category
				Univariate		Multivariate				Univariate		Multivariate				Univariate		Multivariate
Variables		≤T2	>T2	P	OR (95% CI)	P	OR (95% CI)	N0	N1	P	OR (95% CI)	P	OR (95% CI)	M0	M1	P	OR (95% CI)	P	OR (95% CI)
		(n = 54)	(n = 26)					(n = 73)	(n = 9)					(n = 73)	(n = 9)
Sex	Male	13(24.1)	8(30.8)	0.525	0.713 (0.252–2.020)	-	-	19(26.0)	4(44.4)	0.255	0.440 (0.107–1.810)	-	-	20(27.4)	3(33.3)	0.709	0.755 (0.172–3.310)	-	-
	Female	41(75.9)	18(69.2)	0.525	0.713 (0.252–2.020)	-	-	54(74.0)	5(55.6)	0.255	0.440 (0.107–1.810)	-	-	53(72.6)	6(66.7)	0.709	0.755 (0.172–3.310)	-	-
Age (years)	< 55	42(77.8)	12(46.2)	0.006	4.083 (1.498–11.133)	-	-	49(67.1)	6(66.7)	0.978	1.021 (0.235–4.437)	-	-	51(69.9)	4(44.4)	0.138	2.898 (0.710-11.829)	-	-
	≥ 55	12(22.2)	14(53.8)	0.006	4.083 (1.498–11.133)	-	-	24(32.9)	3(33.3)	0.978	1.021 (0.235–4.437)	-	-	22(30.1)	5(55.6)	0.138	2.898 (0.710-11.829)	-	-
Tg (ng/mL)	< 500.00	40(74.1)	9(34.6)	0.001	5.397 (1.963–14.840)	0.001	5.397 (1.963–14.840)	45(61.6)	5(55.6)	0.724	1.286 (0.318–5.197)	-	-	46(63.0)	4(44.4)	0.289	2.130 (0.526–8.619)	-	-
	≥ 500.00	14(25.9)	17(65.4)	0.001	5.397 (1.963–14.840)	0.001	5.397 (1.963–14.840)	28(38.4)	4(44.4)	0.724	1.286 (0.318–5.197)	-	-	27(37.0)	5(55.6)	0.289	2.130 (0.526–8.619)	-	-
TgAb (IU/mL)	< 67.35	40(74.1)	20(76.9)	0.783	0.857 (0.286–2.567)	-	-	54(74.0)	8(88.9)	0.344	0.355 (0.042–3.030)	-	-	56(76.7)	6(66.7)	0.511	1.647 (0.372–7.296)	-	-
	≥ 67.35	14(25.9)	6(23.1)	0.783	0.857 (0.286–2.567)	-	-	19(26.0)	1(11.1)	0.344	0.355 (0.042–3.030)	-	-	17(23.3)	3(33.3)	0.511	1.647 (0.372–7.296)	-	-
TPOAb (IU/mL)	< 25.49	38(70.4)	22(84.6)	0.176	0.432 (0.128–1.455)	-	-	53(72.6)	9(100.0)	0.998	-	-	-	56(76.7)	6(66.7)	0.511	1.647 (0.372–7.296)	-	-
	≥ 25.49	16(29.6)	4(8.1)	0.176	0.432 (0.128–1.455)	-	-	20(27.4)	0(0)	0.998	-	-	-	17(23.3)	3(33.3)	0.511	1.647 (0.372–7.296)	-	-
TSH (µIU/mL)	< 2.208	40(74.1)	21(80.8)	0.511	0.680 (0.215–2.148)	-	-	56(76.7)	6(66.7)	0.511	1.647 (0.372–7.296)	-	-	56(76.7)	6(66.7)	0.511	1.647 (0.372–7.296)	-	-
	≥ 2.208	14(25.9)	5(19.2)	0.511	0.680 (0.215–2.148)	-	-	17(23.3)	3(33.3)	0.511	1.647 (0.372–7.296)	-	-	17(23.3)	3(33.3)	0.511	1.647 (0.372–7.296)	-	-
fT3 (pmol/L)	< 5.50	43(79.6)	18(69.2)	0.309	1.737 (0.600-5.035)	-	-	57(78.1)	5(55.6)	0.150	2.850 (0.684–11.873)	-	-	53(72.6)	9(100.0)	0.998	-	-	-
	≥ 5.50	11(20.4)	8(30.8)	0.309	1.737 (0.600-5.035)	-	-	16(21.9)	4(44.4)	0.150	2.850 (0.684–11.873)	-	-	20(27.4)	0(0)	0.998	-	-	-
fT4 (pmol/L)	< 11.90	43(79.6)	18(69.2)	0.309	1.737 (0.600-5.035)	-	-	55(75.3)	7(77.8)	0.873	0.873 (0.166–4.588)	-	-	54(74.0)	8(88.9)	0.344	0.355 (0.042–3.030)	-	-
	≥ 11.90	11(20.4)	8(30.8)	0.309	1.737 (0.600-5.035)	-	-	18(24.7)	2(22.2)	0.873	0.873 (0.166–4.588)	-	-	19(26.0)	1(11.1)	0.344	0.355 (0.042–3.030)	-	-
fT3/fT4	< 0.541	44(81.5)	17(65.4)	0.118	2.329 (0.807–6.726)	-	-	56(76.7)	6(66.7)	0.511	1.647 (0.372–7.296)	-	-	56(76.7)	6(66.7)	0.511	1.647 (0.372–7.296)	-	-
	≥ 0.541	10(18.5)	9(34.6)	0.118	2.329 (0.807–6.726)	-	-	17(23.3)	3(33.3)	0.511	1.647 (0.372–7.296)	-	-	17(23.3)	3(33.3)	0.511	1.647 (0.372–7.296)	-	-
Abbreviations: Tg, thyroglobulin; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; fT3, free triiodothyronine; fT4, free thyroxine; OR, odds ratio; CI, confidence interval.

Table 5

Logistic regression analysis on indicators of other pathological features
		Lesion						Concomitant PTC
				Univariate		Multivariate				Univariate		Multivariate
Variables		Solitary	Multifocal	P	OR (95% CI)	P	OR (95% CI)	NO	YES	P	OR (95% CI)	P	OR (95% CI)
		(n = 73)	(n = 9)					(n = 72)	(n = 10)
Sex	Male	19(26.0)	4(44.4)	0.255	0.440 (0.107–1.810)	-	-	21(29.2)	2(20.0)	0.549	1.647 (0.322–8.412)	-	-
	Female	54(74.0)	5(55.6)	0.255	0.440 (0.107–1.810)	-	-	51(79.8)	8(80.0)	0.549	1.647 (0.322–8.412)	-	-
Age (years)	< 55	52(71.2)	3(33.3)	0.034	4.952 (1.132–21.661)	0.045	4.756 (1.037–21.818)	47(65.3)	8(80.0)	0.362	0.470 (0.093–2.384)	-	-
	≥ 55	21(28.8)	6(66.7)	0.034	4.952 (1.132–21.661)	0.045	4.756 (1.037–21.818)	25(34.7)	2(20.0)	0.362	0.470 (0.093–2.384)	-	-
Tg (ng/mL)	< 500.00	45(61.6)	5(55.6)	0.724	1.286 (0.318–5.197)	-	-	42(58.3)	8(80.0)	0.204	0.350 (0.069–1.766)	-	-
	≥ 500.00	28(38.4)	4(44.4)	0.724	1.286 (0.318–5.197)	-	-	30(41.7)	2(20.0)	0.204	0.350 (0.069–1.766)	-	-
TgAb (IU/mL)	< 67.35	54(74.0)	8(88.9)	0.344	0.355 (0.042–3.030)	-	-	56(77.8)	6(60.0)	0.229	2.333 (0.586–9.291)	-	-
	≥ 67.35	19(26.0)	1(11.1)	0.344	0.355 (0.042–3.030)	-	-	16(22.2)	4(40.0)	0.229	2.333 (0.586–9.291)	-	-
TPOAb (IU/mL)	< 25.49	53(72.6)	9(100.0)	0.998	-	-	-	56(77.8)	6(60.0)	0.229	2.333 (0.586–9.291)	-	-
	≥ 25.49	20(27.4)	0(0)	0.998	-	-	-	16(22.2)	4(40.0)	0.229	2.333 (0.586–9.291)	-	-
TSH (µIU/mL)	< 2.208	55(75.3)	7(77.8)	0.873	0.873 (0.166–4.588)	-	-	55(76.4)	7(70.0)	0.660	1.387 (0.323–5.957)	-	-
	≥ 2.208	18(24.7)	2(22.2)	0.873	0.873 (0.166–4.588)	-	-	17(23.6)	3(30.0)	0.660	1.387 (0.323–5.957)	-	-
fT3 (pmol/L)	< 5.50	55(75.3)	7(77.8)	0.873	0.873 (0.166–4.588)	-	-	54(75.0)	8(80.0)	0.731	0.750 (0.146–3.862)	-	-
	≥ 5.50	18(24.7)	2(22.2)	0.873	0.873 (0.166–4.588)	-	-	18(25.0)	2(20.0)	0.731	0.750 (0.146–3.862)	-	-
fT4 (pmol/L)	< 11.90	55(75.3)	7(77.8)	0.873	0.873 (0.166–4.588)	-	-	56(77.8)	6(60.0)	0.229	2.333 (0.586–9.291)	-	-
	≥ 11.90	18(24.7)	2(22.2)	0.873	0.873 (0.166–4.588)	-	-	16(22.2)	4(40.0)	0.229	2.333 (0.586–9.291)	-	-
fT3/fT4	< 0.541	58(79.5)	4(44.4)	0.031	4.833 (1.154–20.240)	0.044	4.626 (1.043–20.525)	53(73.6)	9(90.0)	0.281	0.310 (0.037–2.612)	-	-
	≥ 0.541	15(20.5)	5(55.6)	0.031	4.833 (1.154–20.240)	0.044	4.626 (1.043–20.525)	19(26.4)	1(10.0)	0.281	0.310 (0.037–2.612)	-	-
Abbreviations: PTC, papillary thyroid carcinoma; Tg, thyroglobulin; TgAb, thyroglobulin antibody; TPOAb, thyroid peroxidase antibody; TSH, thyroid stimulating hormone; fT3, free triiodothyronine; fT4, free thyroxine.

In our study, elevated preoperative Tg level indicated the patients with more aggressive (non-MI-FTC) and larger (> T2 category) follicular carcinoma. Accidentally, we found the group of older age (≥ 55 years) and the group of higher preoperative fT3\fT4 ratio (≥ 0.541) as an independent risk factors for multifocal FTC, respectively. Therefore, it is necessary to pay attention to these indicators in the management of FTC.

Base on the analysis in this study, we preliminary found the correlation between preoperative serum Tg and pathological features of FTC, which may as a reference in diagnosis and treatment of these tumor. Currently, the value of preoperative serum Tg in the assessment of patients with thyroid nodules was uncertain [8]. First of all, elevated serum Tg level could help identify DTC in some preview studies [9–11]. However, Tg is not a recognized serum marker of DTC due to the interference of various common thyroid benign diseases [12, 13], and the lack of more prospective studies to support it [8]. Besides, other studies have reported the association between preoperative serum Tg and postoperative pathology in patients with DTC. Several studies have found that the burden or extent of DTC increased with increasing preoperative Tg level, which may indicate the more extensive local infiltration [4, 14], the larger primary tumor diameter [4, 14, 15], the presence of cervical lymph node metastasis [4, 14, 16], and the presence of distant metastasis [4, 17, 18]. Nonetheless, because of the considerable differences in the incidence rates, PTC accounted for the major subjects of these studies and FTC was slightly ignored. Recently, some researchers found that the patients with FTC had higher preoperative serum Tg level than those with non-FTC nodules [19]. In addition, other researchers found that higher preoperative Tg level was a potential diagnostic tool in patients with thyroid follicular neoplasm [20–22]. Furthermore, in this study, we focused on the relationship between preoperative serum markers and postoperative pathological features of FTC patients, and found that elevated preoperative serum Tg level indicated the more extensive local infiltration (non-MI-FTC) and the larger primary tumor diameter (> T2 category) in follicular carcinoma.

Of course, serum Tg is more commonly used as a prognostic marker for the follow-up of DTC patients after total thyroidectomy [12]. Interestingly, combined with our results and related evidences, serum Tg may have unique preoperative value for the patients with FTC.

The association between thyroid autoimmunity and thyroid cancer has been discussed repeatedly [23, 24]. The study regarding serological differences in follicular neoplasm found that preoperative serum TgAb was an independent risk factor for FTC [21], while there was no association between preoperative thyroid autoimmune antibody and specific pathological features of FTC in this study.

In our analysis, the group of age (≥ 55 years) and the group of preoperative fT3\fT4 ratio (≥ 0.541) were associated with the number of lesions in FTC, but other thyroid function indicators (TSH, fT3, and fT4) were unrelated to the pathological features of FTC. In recent years, a few studies showed that high fT3/fT4 ratio predicted a favorable prognosis for certain cancers [25, 26] as well as a low risk of recurrence of PTC [27]. In contrast, this study found that elevated fT3\fT4 ratio (≥ 0.541) indicated the patients with multifocal FTC, which was a statistical result only and could not be explained clinically.

Some limitations of our study should be considered. First, this was a retrospective single-center study with small sample size. Second, the patients with preoperative metastasis may be underestimated because the tumor metastasis was only defined by reviewing their preoperative medical data in our center. Third, the patients with positive serum TgAb accounted for 17.1% (14/82), which may be interfering with detection of the serum Tg. Fourth, the display range for serum Tg level is 0.05–500.00 ng/mL, for serum TgAb level is higher or equal to 10.00 IU/mL, and for serum TPOAb level is higher or equal to 5.00 IU/mL in our center. For analyses, Tg level < 0.05 ng/mL and > 500 ng/mL were considered to be 0.05 ng/mL and 500 ng/mL, respectively; TgAb level < 10.00 IU/mL was considered to be 10.00 IU/mL; TPOAb level < 5.00 IU/mL was considered to be 5.00 ng/mL.

In conclusion, preoperative serum Tg was correlated with the local tumor extent and primary tumor diameter of FTC. Further research regarding the utility of preoperative serum Tg in FTC is still needed in the future.

Acknowledgments:

This work did not receive any funding.

Data Availability Statement:

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

Achebrook-Kilfoy B, Grogan RH, Ward MH, Kaplan E, Devesa SS. Follicular thyroid cancer incidence patterns in the United States, 1980-2009. Thyroid. 23:1015-1021 (2013)
Grani G, Lamartina L, Durante C, Filetti S, Cooper DS. Follicular thyroid cancer and Hurthle cell carcinoma: Challenges in diagnosis, treatment, and clinical management. Lancet. Diabetes. Endocrinol. 6:500-514 (2018)
Perrier ND, Brierley JD, Tuttle RM. Differentiated and anaplastic thyroid carcinoma: Major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA. Cancer. J. Clin. 68(1):55-63 (2018)
Kim H, Park SY, Choe JH, et al. Preoperative Serum Thyroglobulin and Its Correlation with the Burden and Extent of Differentiated Thyroid Cancer. Cancers. (Basel). 8;12(3):625 (2020)
Lee ZJO, Eslick GD, Edirimanne S. Investigating Antithyroglobulin Antibody As a Prognostic Marker for Differentiated Thyroid Cancer: A Meta-Analysis and Systematic Review. Thyroid. 30(11):1601-1612 (2020)
McLeod DSA, Bedno SA, Cooper DS, et al. Pre-existing Thyroid Autoimmunity and Risk of Papillary Thyroid Cancer: A Nested Case-Control Study of US Active-Duty Personnel. J. Clin. Oncol. 13:JCO2102618 (2022)
McLeod DS, Cooper DS, Ladenson PW, et al. Prognosis of differentiated thyroid cancer in relation to serum thyrotropin and thyroglobulin antibody status at time of diagnosis. Thyroid. 24(1):35-42 (2014)
Li S, Ren C, Gong Y, et al. The Role of Thyroglobulin in Preoperative and Postoperative Evaluation of Patients With Differentiated Thyroid Cancer. Front. Endocrinol. (Lausanne). 2;13:872527 (2022)
Scheffler P, Forest VI, Leboeuf R, et al. Serum thyroglobulin improves the sensitivity of the McGill Thyroid Nodule Score for well-differentiated thyroid cancer. Thyroid. 24(5):852-857 (2014)
Rinaldi S, Plummer M, Biessy C, et al. Thyroid-stimulating hormone, thyroglobulin, and thyroid hormones and risk of differentiated thyroid carcinoma: the EPIC study. J. Natl. Cancer. Inst. 106(6):dju097 (2014)
Kars A, Aktan B, Kilic K, et al. Preoperative Serum Thyroglobulin Level as a Useful Predictive Marker to Differentiate Thyroid Cancer. ORL. J. Otorhinolaryngol. Relat. Spec. 80(5-6):290-295 (2018)
Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 26(1):1-133 (2016)
Kang M, Wang TS, Yen TW, Doffek K, Evans DB, Dream S. The Clinical Utility of Preoperative Thyroglobulin for Surgical Decision Making in Thyroid Disease. J. Surg. Res. 270:230-235 (2022)
Noel JE, Thatipamala P, Hung KS, Chen J, Shi RZ, Orloff LA. Pre-Operative Antithyroid Antibodies in Differentiated Thyroid Cancer. Endocr. Pract. 27(11):1114-1118 (2021)
Patell R, Mikhael A, Tabet M, Bena J, Berber E, Nasr C. Assessing the utility of preoperative serum thyroglobulin in differentiated thyroid cancer: a retrospective cohort study. Endocrine. 61(3):506-510 (2018)
Huang Z, Song M, Wang S, et al. Preoperative Serum Thyroglobulin Is a Risk Factor of Skip Metastasis in Papillary Thyroid Carcinoma. Ann. Transl. Med. 8(6):389 (2020)
Oltmann SC, Leverson G, Lin SH-I, Schneider DF, Chen H, Sippel RS. Markedly elevated thyroglobulin levels in the preoperative thyroidectomy patient correlates with metastatic burden. J. Surg. Res. 187(1):1-5 (2014)
Kim H, Kim YN, Kim HI, et al. Preoperative Serum Thyroglobulin Predicts Initial Distant Metastasis in Patients With Differentiated Thyroid Cancer. Sci. Rep. 7(1):16955 (2017)
Yu Q, Liu K, Xie C, et al. Development and validation of a preoperative prediction model for follicular thyroid carcinoma. Clin. Endocrinol. (Oxf). 91(2): 348-355 (2019)
Hocevar M, Auersperg M. Role of serum thyroglobulin in the pre-operative evaluation of follicular thyroid tumours. Eur. J. Surg. Oncol. 24(6):553-557 (1998)
Petric R, Perhavec A, Gazic B, Besic N. Preoperative serum thyroglobulin concentration is an independent predictive factor of malignancy in follicular neoplasms of the thyroid gland. J. Surg. Oncol. 15;105(4):351-356 (2012)
Chen Z, Lin Y, Lai S, et al. The utility of serum anti-thyroglobulin antibody and thyroglobulin in the preoperative differential diagnosis of thyroid follicular neoplasms. Endocrine. 76(2):369-376 (2022)
Boi F, Pani F, Mariotti S. Thyroid Autoimmunity and Thyroid Cancer: Review Focused on Cytological Studies. Eur. Thyroid. J. 6(4):178-186 (2017)
Nagayama Y. Thyroid Autoimmunity and Thyroid Cancer - The Pathogenic Connection: A 2018 Update. Horm. Metab. Res. 50(12):922-931 (2018)
Pasqualetti G, Schirripa M, Dochy E, et al. Thyroid hormones ratio is a major prognostic marker in advanced metastatic colorectal cancer: Results from the phase III randomised CORRECT trial. Eur. J. Cancer. 133:66-73 (2020)
Maruzzo M, Verzoni E, Vitale MG, et al. Prognostic Value of Thyroid Hormone Ratio in Patients With Advanced Metastatic Renal Cell Carcinoma: Results From the Threefour Study (Meet-URO 14). Front. Oncol. 25;11:787835 (2021)
Liu Y, Huang Y, Mo G, et al. Combined prognostic value of preoperative serum thyrotrophin and thyroid hormone concentration in papillary thyroid cancer. J. Clin. Lab. Anal. 6:e24503 (2022)

Supplementary.docx

The correlation between preoperative serum thyroglobulin and pathological features of thyroid follicular carcinoma

Status:

Version 1

Abstract

Introduction

Materials And Methods

Results

Discussion

Declarations

References

Supplementary Files

Status:

Version 1