Preoperative Serum Thyroglobulin Levels Predict Radioiodine Therapy Outcome in Papillary Thyroid Microcarcinoma Patients

Abstract

Our previous study showed that elevated preoperative thyroglobulin (pre-Tg) level predicted the risk of developing radioiodine refractory in PTC patients. In the present study, we aimed to evaluate the prognostic value of pre-Tg in papillary thyroid microcarcinoma (PTMC). After a specific inclusion and exclusion criteria were applied, a total of 788 PTMCs were enrolled from Jiangyuan Hospital affiliated to Jiangsu Institute of Nuclear Medicine between Jan 2015 and Dec 2019. Among them, 107 PTMCs were treated with radioiodine therapy (RAIT) and the response to therapy was grouped as excellent response (ER), and non-excellent response (NER: indeterminate response, IDR and biochemical incomplete response, BIR). Multivariable logistic regression was used to identify predictors for the response of RAIT in PTMCs. Higher pre-Tg levels were detected in PTMCs with RAIT as compared with PTMCs without RAIT (p=0.0018). Higher levels of pre-Tg were also found in patients with repeated RAIT as compared with patients with single RAIT (p<0.0001). Furthermore, pre-Tg level was higher in PTMC with IDR (n=16) and much higher in BIR (n=9) as compared with patients with ER (n=82, p=0.0003) after RAIT. Multivariate analysis showed that pre-Tg level over 16.79 ng/ml [OR: 6.55 (2.10–20.39), p=0.001] was the only independent predictor for NER in PTMC with RAIT. We found that high level of pre-Tg predicted a poor RAIT outcome in PTMC. Our finding explores a prospective way in identifying high-risk PTMCs with poor response to RAIT.

 

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Keywords

PTMC - preoperative thyroglobulin - radioiodine therapy - prognosis

Introduction

Papillary thyroid microcarcinoma (PTMC) is commonly referred to as papillary thyroid carcinoma (PTC) with a maximal diameter of≤10 mm. Despite its prevalence, most PTMCs behave in an indolent way and typically have good prognoses [1]. For those low-risk PTMC, active surveillance (AS) or other non-surgery methods were accepted as an alternative management option according to the 2015 American Thyroid Association (ATA) guidelines [2]. For PTMC patients with lymph node metastasis (LNM), or extrathyroidal extension (ETE), traditional treatment including surgery and postoperative radioactive iodine therapy (RAIT) will be implemented, if necessary [2]. However, poor response to RAIT and risk of recurrence still exists in PTMC after routine therapy [3] [4] [5]. Identifying predictors in risk stratification of PTMC with poor prognosis will provide great supports for the decision making of AS or treatment management for PTMC patients. Up to date, only few risk factors like age<40, male gender, multifocality, and calcification have been reported to be associated with high-risk clinical features [6] and therefore more efforts are needed to uncover some other risk factors for early identifying PTMC with poor prognosis.

Thyroglobulin (Tg) is synthesized in thyroid follicular cells under the regulation of thyroid stimulating hormone (TSH) [7]. In healthy individuals, serum Tg is barely detectable. The level of Tg was applied in an attempt to the field of thyroid cancer diagnosis at first but it failed due to the overlap between benign and malignant thyroid tissues [2]. However, recent findings showed an association of pre-Tg with the poor prognosis of thyroid cancer like LNM, distant metastasis, and so on [8] [9] [10]. Besides, our recent study provoked a prognostic value of pre-Tg in classifying patients with risk of radioiodine refractory (RAIR) [11]. Interestingly, we also noticed a relative high level of pre-Tg in a small number of PTMC patients with RAIR [11]. It is well-known that Tg level may be influenced by certain factors like antibodies of Tg (TgAb) and thyroiditis like Hashimoto’s thyroiditis (HT) [2]. Whether pre-Tg has a predictive value in PTMC after the exclusion of these interference factors remains unknown.

Here, we compared the pre-Tg level in patients with or without radioiodine therapy (RAIT), or with single and multiple cycles of RAIT. Furthermore, the association of pre-Tg level and the response to RAIT in PTMC were investigated. Our study provoked pre-Tg as a novel predictor for PTMC prognosis and may shed light on the choice of personalized management of PTMC in the future.

 

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Subjects and Methods

Study participants

This retrospective study was conducted in Jiangyuan Hospital affiliated to Jiangsu Institute of Nuclear Medicine. Preoperative thyroid ultrasonography (US), and thyroid function test were done routinely. Based on the clinical decision-making framework suggested by Brito et al., patients were evaluated for the options of management [12]. For low-risk PTMC, both lobectomy and active surveillance were suggested in our hospital.

 

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Exclusion criteria

There were 4482 PTMC patients who underwent thyroid surgery from January 2015 to December 2019 in our hospital. After the exclusion of patients with anti-thyroglobulin antibody (TgAb) positive, thyroiditis, history of fine needle aspiration (FNA), and less than 1-year follow-ups, etc., 788 PTMCs with full records including pre-Tg, TgAb, thyroid stimulating hormone (TSH), and post-surgery Tg were enrolled. The follow-up time course was decided as the period from surgery to the index date. Each index date for each patient was referred to the latest laboratory results from January 2015 to December 2022. The median follow-up was 67.55 (range 49.53–80.64) months.

 

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Surgery and RAIT

Lobectomy was conducted in 496 PTMCs, and total thyroidectomy was done in 292 patients. A total of 107 patients were treated with RAI after undergoing total thyroidectomy. ATA risk stratification was determined based on 2015 ATA guidelines [2]. For partial PTMC patients with intermediate risk and high risk, an empirical dose of 100–250 millicurie (mCi, 3.7–9.25 gigabecquerel, GBq) was administrated. All patients were recommended to have 6- and 12-month follow-ups after RAIT.

The response to RAIT was evaluated based on 2015 ATA guidelines [2]. Briefly, the response to RAIT was determined based on their imaging and serologic results. Then it was subscribed into excellent response (ER), and non-excellent response (NER), which includes indeterminate response (IDR), biochemistry recurrence (BIR), and structurally recurrence (SIR). After 1-year follow-up [13.2 (10.0–15.1) months], 76/107 patients exhibited an ER, 15/107 patients developed a IDR, and 16/107 patients developed a BIR. At the last follow-up [51.5 (32.3–66.9) months], 82/107 patients showed ER, 16/107 patients showed IDR, 8 patients developed BIR, and 1/107 patient developed SIR. The only SIR patient was classified in the BIR group in the current study.

 

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Variables

Electronic clinical documentation, pathologic information, laboratory data, surgical reports, radiology reports, and molecular testing results were obtained from Jiangyuan Hospital electronic information system if possible. With the approval of the institutional ethics committee (YL202207), the clinical data of patients were carefully reviewed.

Age was recorded on the date of diagnosis, and the cut-off age for risk stratification was set at 55 years according to the Eighth Edition of the American Joint Committee on Cancer [13]. All involved PTMC were classical PTMC. Gross ETE was defined as the macroscopic extension of the primary tumor into the perithyroidal tissues including strap muscles, trachea, recurrent laryngeal nerve, and blood vessel. Positive LNM was defined as the number over 5 LNMs [2].

Tg, TgAb, TPOAb, and TSH of patients before surgery were measured by a clinical laboratory using Cobas 8000 modular analyzer series with indicated immunochemiluminescence assay kits according to the manufacturer’s instructions (Roche, Mannheim, Germany). The quantification limits of Tg and TgAb, TPOAb measurements were from 0.04–500 ng/ml, 0–115 IU/ml and 0–34 IU/ml, respectively. The normal or reference range for TSH was 0.35 to 5.5 mIU/l in this study. The normal range for TgAb was below 115 IU/ml, and the normal range for TPOAb was below 34 IU/ml.

 

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Statistical analysis

Normally distributed continuous variables are expressed as mean±standard deviation (SD) and compared using the independent-sample t-test. Non-normally distributed continuous variables are presented as median with interquartile range (IQR) and compared using the Mann–Whitney U-test. Categorical variables were presented as numbers with percentages and compared using Chi-square and Fisher’s exact methods. For receiver operating characteristic (ROC) analysis, GraphPad Prism 8.2.1 was used to draw a ROC curve and the optimal cut-off value of pre-Tg for predicting the prevalence of RAIT was selected. For multivariate analysis, binary logistic regression with the forward LR method was performed for all demographic and pathologic variables. A two-sided p<0.05 was considered statistically significant.

 

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Results

High level of pre-operative Tg was found in PTMC with repeated RAIT

This study included 788 PTMC patients (590 women, and 198 men) according to the inclusion criteria ([Fig. 1]). A total of 91 patients received single RAIT and 16 patients received multiple cycles of RAIT. The patients’ baseline characteristics are shown in [Table 1]. All clinical pathologic factors showed significant differences between groups of patients with or without RAIT (p<0.001). When comparing patients with single or multiple cycle of RAIT, no clinical factors showed difference except factors of LNM (p=0.03) and LNM number over 5 (p<0.001).

Fig. 1 Flow chart of the study. The cohort included 4482 patients with PTMC. After the inclusion/exclusion criteria were applied, 788 PTMC patients were finally involved.

Table 1 Clinicopathological characteristics of the papillary thyroid microcarcinoma patients.

Variables	No RAIT	Single RAIT	Repeated RAIT	p-Valuea	p-Valueb
Number of cases	681	91	16
Median age (years)	44 (35, 52)	46 (38, 52.5)	37 (32.25, 44)
Age at diagnosis (years)				0.922	0.22
<55	569 (83.6)	74 (81.3)	15 (93.8)
≥55	112 (16.4)	17 (18.7)	1 (6.3)
Sex				0.612	0.69
Female	512 (75.2)	67 (73.6)	11 (68.8)
Male	169 (24.8)	24 (26.4)	5 (31.2)
Maximum tumor size (cm)				<0.001	0.91
<0.5	254 (37.3)	16 (17.6)	3 (18.8)
≥0.5	427 (62.7)	75 (82.4)	13 (81.2)
Multifocality				<0.001	0.13
Yes	154 (22.6)	63 (69.2)	8 (50.0)
No	527 (77.4)	28 (30.8)	8 (50.0)
Gross ETE				<0.001	0.47
Yes	22 (3.2)	11 (12.1)	3 (18.8)
No	659 (96.8)	80 (87.9)	13 (81.2)
LNM				<0.001	0.03
Yes	215 (31.6)	70 (76.9)	16 (100.0)
No	466 (68.4)	21 (23.1)	0 (0)
LNM (n>5)				<0.001	<0.001
Yes	24 (3.5)	27 (29.7)	8 (50.0)
No	657 (96.5)	64 (70.3)	8 (50.0)
Tumor laterality				<0.001	0.34
Unilateral	479 (70.3)	13 (14.3)	13 (81.2)
Bilateral	202 (29.7)	78 (85.7)	3 (18.8)
BRAF V600E c				0.418	0.18
Yes	77 (96.2)	7 (100)	3 (75.0)
No	3 (3.8)	0 (0)	1 (25.0)
ATA risk after surgery				<0.001	1.00
Low	399 (58.6)	0 (0)	0 (0)
Intermediate+High	282 (41.4)	91 (100)	16 (100.0)
Accumulated 131 I doses	0	120 (100–135)	300 (230–320)	–	<0.001
Median follow-up time (months)	64.3 (48.8–79.2)	78.7 (60.2–87.8)	73.9 (53.9–86.5)

^a p-Value was compared between patients without RAIT and with RAIT. Pearson Chi-Square value. ^b p-Value was compared between patients with single and repeated RAIT. Pearson Chi-Square value. ^c BRAF mutation, partial data available, n=91.

However, the level of pre-Tg was higher in the RAIT group. The median levels of pre-Tg for each group were as follows: 10.63 (range 5.4–20.1) ng/ml in the no-RAIT group, 16.5 (range 6.6–40.5) ng/ml in the RAIT group (p=0.0018). Further, the level of pre-Tg was much higher in patients with repeated RAIT. The median levels of pre-Tg for each group were as follows: 12.86 (5.19–27.8) ng/ml in single RAIT group, and 40.67 (21.77–83.46) ng/ml in repeated RAIT group ([Fig. 2]).

Fig. 2 High level of pre-Tg in PTMC with repeated RAIT. a: Scatter plots with histograms of pre-Tg levels in groups of patients with or without RAIT. Mann–Whitney U-test, p=0.0018. b: Scatter plots with histograms of pre-Tg in patients with 1 cycle or>1 cycle of RAIT. Mann–Whitney U-test, p<0.0001.

 

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Higher pre-operative Tg was found in PTMCs with poor prognosis after RAIT

Among 107 PTMC patients with RAIT, 82 patients showed ER, 16 patients showed IDR, and 9 patients showed BIR at the last follow-up. The median value of pre-Tg was 11.8 (range 4.7–25.4) ng/ml in the ER group, 21.5 (range 9.5–75.0) ng/ml in the IDR group and 59.5 (range 39.4–143.4) ng/ml in the BIR group (p=0.0003) ([Fig. 3a]).

Fig. 3 Higher level of pre-Tg in patients with IDR and BIR. a: Scatter plots of pre-Tg in patients with excellent response (ER), indeterminate response (IDR) or biochemical incomplete response (BIR). Mann–Whitney U-test, p=0.0003. b: ROC curve for pre-Tg in PTMC patients with NER, p=0.0006.

To evaluate the predictive performance of pre-Tg for RAIT outcome (ER and NER) in PTMCs, the ROC curve was fitted and the corresponding area under curve (AUC) was 0.73 (0.61–0.85, p=0.0006). Setting the cut-off point of pre-Tg at 16.79 ng/ml gained a maximum 80.0% (59.3–93.2%) in sensitivity and 61.0% (49.6–71.6%) in specificity.

 

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Pre-operative Tg was the independent predictor for poor prognosis of RAIT in PTMCs

In univariate analysis, factors found with statistical significance in predicting NER were as follows: LNM number over 5 (OR=2.96; 95% CI, 1.17–7.44; p=0.022), bilaterality (OR=0.33; 95% CI, 0.12–0.94; p=0.039), and pre-Tg over 16.79 ng/ml (OR=6.25; 95% CI, 2.13–18.33; p<0.001). When taken these factors in further multivariate analysis, only pre-Tg over 16.79 ng/ml (OR=5.91; 95% CI, 1.96–17.83; p=0.002) was the independent predictor for NER in PTMC patients with RAIT ([Table 2]).

Table 2 Univariate and multivariate analysis of the risk factors of NER in patients with RAIT.

Variables	Univariate analysis		Multivariate analysis
	OR (95% CI)	p value	OR (95% CI)	p-Value
Sex (Male)	2.21 (0.85–5.72)	0.102	–	–
Age (≥55)	0.36 (0.08–1.68)	0.193	–	–
Tumor size (≥0.5 cm)	1.18 (0.35–3.93)	0.793	–	–
Multifocality (Yes)	0.45 (0.18–1.12)	0.087	–	–
Gross ETE (Yes)	2.02 (0.61–6.73)	0.248	–	–
LNM (n>5)	2.96 (1.17–7.44)	0.022	2.31 (0.83–6.41)	0.109
Bilaterality (Yes)	0.33 (0.12–0.94)	0.039	0.43 (0.13–1.41)	0.164
Pre-Tg (≥16.79 ng/ml)	6.25 (2.13–18.33)	<0.001	5.91 (1.96–17.83)	0.002

OR: Odds Ratio; pre-Tg: preoperative Tg.

 

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Discussion

In the current study, we showed that a high level of pre-Tg was found in PTMC patients with RAIT, repeated RAIT and poor response to RAIT. In comparison of PTMC patients with ER at the last follow-up, pre-Tg level was higher in patients with NER. All these results provided pre-Tg as a feasible biomarker in evaluating PTMC patients with the risk of poor prognosis. Consistently, more and more studies showed that pre-Tg was closely related with the prognosis of thyroid cancer. Our previous study showed that high level of pre-Tg>70.05 ng/ml in PTC was a prognostic marker for the development of RAIR [11]. Likewise, high serum pre-Tg level has been provoked to be associated with tumor metastasis in PTC [9] [14] [15] [16]. In FTCs, pre-Tg was also regarded as a valuable predictor for distant metastasis [15]. Although pre-Tg can not better discriminate benign nodule from thyroid cancer, it is more acceptable that the level of pre-Tg was a promising biomarker for thyroid cancer prognosis.

Risk factors like age<40, male gender, multifocality, and calcification were found to be correlated with LNM in PTMC [6]. However, the occurrence of LNM was not closely related with the prognosis and most small metastatic cervical LNs remained stable during AS in PTMC [17]. Similarly, our results showed that LNM number over 5 was not an independent risk factor for PTMC prognosis but we found it was correlated with the response to RAIT. In the current study, our conclusion might be influenced by the small sample size and more efforts were needed to verify the correlation of LNM with PTMC progression.

Whether patients can benefit from repeated RAIT is still in controversy. One report pointed out that a second RAIT hardly benefited thyroid cancer patients [18]. Similarly, we also found a high consistency in the response to RAIT at the time of one-year follow-up and the last follow-up. Limited number of patients were benefited from the second or more cycles of therapy. This observation may be influenced by the time of Tg measurement and needed to be further confirmed.

In recent years, active surveillance (AS) has been endorsed as an alternative management approach for upfront surgical treatment in low-risk PTMC [19]. It markedly decreased the side effects like alterations in voice associated with damage to recurrent and superior laryngeal nerves, hypoparathyroidism caused by the surgery [20]. Thus, the 2016 Chinese medical expert consensus recommended AS for patients with low-risk PTMC [21]. However, like in our cohort, there were still a considerable number of PTMC patients with lobectomy even they have a good prognosis within the 5-year follow-up. Barriers were caused by the complexity in the decision-making process and the nature fear of cancer in patients [22] [23] [24]. Enhancing the consensus among clinicians and informational supports for patients will largely improve the ratio of PTMC with AS when applicable. Meanwhile, a feasible biomarker to distinguish the aggressive PTMC will strengthen the confidence of clinicians and patients when facing the choice making from AS and upfront surgery.

BRAF V600E mutation molecular test has been widely used in identifying malignant thyroid cancer [2]. It may be promising to combine the use of BRAF V600E and pre-Tg in predicting PTMC patient prognosis. By distinguishing PTMC patients with poor prognosis, it may also help in the decision making of AS for patients with fear of disease progression.

Limitations

Our study has several limitations. First of all, due to the low prevalence of high-risk features in PTMC, a limited eligible sample size of PTMC with repeated RAIT and poor response to RAIT was enrolled in our cohort.

Second, the cycles of RAIT received by patients and the response to RAIT used in the present study cannot best reflect the recurrence and progression of PTMC. It still needs more studies concerning the real state of recurrence and metastasis in PTMC, though its incidence is low, to verify the prognostic role of pre-Tg.

More importantly, the underlying mechanism that why high pre-Tg level correlated with poor prognosis of PTMC remained elusive. We have excluded the interference of thyroiditis, TgAb, and other possible factors. However, we only found a weak correlation of pre-Tg and LNM number over 5 (data not shown). One study has also pointed out the correlation of pre-Tg and LNM by establishing a nomogram model for the prediction of cervical and lateral LNM based on serum pre-Tg levels [25]. It still needs more efforts to uncover the mechanism leading to the upregulation of pre-Tg in patients with risk of poor prognosis.

Also, the selection bias could not be neglected, and more studies were needed to confirm our conclusion.

In summary, our results showed a high level of pre-Tg in patients with poor prognosis in PTMC. It can offer a new prognostic marker for PTMC with RAIT.

 

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Conflict of Interest

The authors declare that they have no conflict of interest.

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Publication History

Received: 22 September 2023

Accepted after revision: 19 March 2024

Accepted Manuscript online:
19 March 2024

Article published online:
15 April 2024