Predictive Value and Dynamic Risk Stratification of High Sensitive Basal or Stimulated Thyroglobulin Assay in a Long-term Thyroid Carcinoma Cohort

doi:10.21203/rs.3.rs-2238203/v1

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Research Article

Predictive Value and Dynamic Risk Stratification of High Sensitive Basal or Stimulated Thyroglobulin Assay in a Long-term Thyroid Carcinoma Cohort

https://doi.org/10.21203/rs.3.rs-2238203/v1

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published 23 Feb, 2023

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Purpose

To evaluate the predictive value and Dynamic Risk Stratification (DRS) of rhTSH-thyroglobulin (Tg) and highly sensitive basal Tg (hs-Tg) measurements at 12 months after completion of initial treatment in a Differentiated Thyroid Carcinoma (DTC) cohort.

Methods

Prospective study in all 114 patients diagnosed of DTC (77.2% women) from 2014 to 2020 undergoing total thyroidectomy and radioiodine ablation in whom hs-Tg and rhTSH-Tg was performed 12 months after completing initial treatment. Mean age was 46.4 ± 14.1 with a follow-up of 7.9 ± 5.9 years. We evaluated the ability of both tests to predict the long-term response and DRS at the last follow-up visit.

Results

hs-Tg and rhTSH-Tg show a strong positive lineal correlation r = 0.864,p < 0,001. The diagnostic performance of initial hs-Tg and rhTSH-Tg levels were evaluated via ROC-AUC as a predictor of Excellent Response (ER) in last follow-up visit. Hs-Tg showed a better AUC (0.969,95%CI = 0.941–0.997) than rhTSH-Tg (0.944,95%IC = 0.905–0.984);p < 0.001. The hs-Tg and rhTSH-Tg cutoff point of highest sensitivity (S) and specificity (E) was 0.110 and 0.815ng/dl, respectively. Hs-Tg showed a higher diagnostic accuracy than rhTSH-Tg (S = 100%vs96.8%, E = 84.3%vs84.3%, NPV = 100%vs98.6%, PPV = 70.5%vs69.7%;p < 0.05). The DRS based on initial hs-Tg showed better ability to predict ER (93.3% vs 86.7%) and biochemical incomplete response (53.3%vs13.3%) in the last follow-up visit than rhTSH-Tg.

Conclusions

Initial hs-Th and rhTSH-Tg were a good predictor of long-term ER. In patients with hs-Tg, the rhTSH-test did not provide relevant diagnostic information. An ER after initial treatment was associated with a very high NPV at subsequent follow-up.

Dynamic Risk Stratification

Thyroid cancer

thyroglobulin

excellent response

Even though differentiated thyroid carcinoma (DTC) is the most frequent malignant endocrine neoplasia, the prevalence in general population is less than 1%, mostly affecting middle aged women, generally showing an excellent prognosis [1]. In this context, international clinical guidelines have been modifying their protocols for diagnosis, treatment and follow-up of the thyroid nodule and DTC towards less aggressive ways of control (2).

Classically, long-term management of DTC after total thyroidectomy used to involve ablative treatment with I131 and suppression therapy of TSH levels with levothyroxine at supraphysiologic doses in virtually all patients. Besides, a long-term clinical follow-up program was considered mandatory to detect persistent or recurrent disease by performing total body I131 scans, cervical ultrasound and thyroglobulin (Tg) and anti-thyroglobulin antibodies (AbTg) levels every 6–12 months [2]. However, nowadays, the greater sensitivity of Tg assays and cervical ultrasound imaging have reduced the usefulness of remaining techniques to special situations (presence of positive AbTg, diagnostic doubts, among others) [2, 3].

Secondly, the predictive survival models in DTC based exclusively on initial diagnostic factors have proven to be insufficient for long-term assessment due to their static nature [4]. The development of a Dynamic Risk Stratification (DRS) model in DTC has allowed to evaluate the disease status all along the disease evolution. The DRS assesses the treatment response at any time, the DTC biological/histological features, as well as the minimum follow-up required [5].

In particular, Tg is a glycoprotein that is exclusively synthesized in the thyroid follicular cell. Therefore, it is the essential marker of persistence/recurrence in DTC. In this context, undetectable Tg values (with negative AbTg) rule out the active disease status in those patients who underwent total thyroidectomy and I131 ablative dose. In contrast, measurable Tg levels suggest a recurrent or persistent disease status [6].

However, due to the low analytical functional sensitivity of first generation Tg assays, their determination required the stimulation of basal Tg levels under TSH suppressive therapy by prolonged thyroid hormone withdrawal (THW) or through the administration of recombinant human TSH (rhTSH), to assure enough sensitivity. In fact, the 2015 American Thyroid Association (ATA) Clinical Guideline recommended that all patients should undergo Tg stimulation tests 6 to 12 months after I131 ablation therapy [2]. However, both stimulation procedures are uncomfortable for the patient, time consuming and require strict protocols with a high cost of human and economic resources.

Recently, high-sensitivity Tg assays (hs-Tg) have been developed with a 10-fold higher capacity to detect serum Tg values than conventional assays. The use of hs-Tg in DTC may be associated with some advantages as avoiding the use of stimulated Tg test [7] or an earlier detection of recurrence [8]. However, this additional sensitivity may present some disadvantages such as the detection of small levels of serum Tg with no clear clinical implication, which may normalize spontaneously over time. In addition, the DRS may use either basal or stimulated Tg levels for its classification, and differences in staging can be observed depending on the specific Tg evaluated. The clinical implications of these divergences are currently unknown.[2].

The aim of the present study was to evaluate the ability of rhTSH-Tg stimulation test compared to basal hs-Tg under TSH suppressive therapy at 12 months after completion of initial treatment to predict the long-term response and DRS at the last follow-up visit in a long-term DTC cohort.

A prospective longitudinal cohort study was carried out in all patients with DTC in follow-up on the Thyroid Nodule and Cancer Clinic on the Endocrinology and Nutrition Department at a Tertiary Hospital. All DTC with rhTSH stimulation test performed 12 months after completing initial treatment (thyroidectomy and I131 ablation) from 2014 to 2021 were included.

The following clinical data were collected: age at diagnosis, year of thyroid cancer diagnosis, duration of clinical course in months from the diagnosis to the last visit, type and characteristics of the thyroid cancer diagnosed: size in centimeters, multifocality, capsular and vascular invasion, and TNM staging. In addition, the following were recorded: risk of recurrence following diagnosis (excluding molecular markers), and DRS at 12 months after completing the initial treatment and at the last monitoring visit, according to the ATA 2015 guideline [2], in those patients who underwent surgery with total thyroidectomy and ablation with radioactive iodine.

Histological classification was performed according to the WHO classification [9] in 2 main categories: papillary carcinoma and follicular carcinoma. The latter includes minimally and widely invasive variants, the clear cell variant and Hürthle cell carcinomas (or oncocytic variant). Histologic variants of papillary carcinoma were grouped into 3 categories: classic papillary carcinomas, follicular variant papillary carcinomas and the most aggressive histologic variants (diffuse sclerosing, solid-trabecular, tall cell and columnar cell subtypes). Tumors were classified at diagnosis according to the 8th edition of the American Joint Committee of Cancer TNM classification [10].

Laboratory parameters for DTC monitoring were analysed by electrochemiluminescence immunoassay with the same methodology throughout the entire follow-up (ECLIA) (Roche Diagnostics, Geneva, Switzerland). In particular: second-generation plasma Tg, AbTg and circulating TSH levels 12 months after completing initial treatment and at the last follow-up visit on levotiroxine treatment.

Plasma basal and stimulated Tg were determined 12 months after completing initial treatment (total thyroidectomy and ablation with I131) using the second-generation ultrasensitive immunoassay Elecsys® on Cobas® e801 according to the manufacturer's instructions (Roche Diagnostics, Geneva, Switzerland). We adopted as a positive serum Tg result the functional sensitivity (FS) of the test (0.1 µg/L), understood as the minimum concentration of Tg that can be evaluated with an inter-test imprecision (CV) < 20%, with Tg values < 0.1 µg/L being considered undetectable.

The rhTSH stimulation test consisted of the administration of an intramuscular injection of rhTSH (0.9 mg im, Thyrogen®; Genzyme Cambrige, USA) for 2 consecutive days. Serum samples for measurement of TSH, Tg and AgTb were collected on the first day of the stimulation test, immediately before the rhTSH injection and 3 days after the second rhTSH injection. In addition, to verify adequate stimulation with rhTSH, TSH levels were determined 72 hours after the first rhTSH injection.

All patients signed an informed consent for their inclusion before participating in the study. The protocol was approved by the Clinical Research Ethics Committee of the Hospital Center and the study was conducted in accordance with the Declaration of Helsinki.

Statistical analysis

The results were expressed in terms of mean and standard deviation (SD) and qualitative variables were expressed in terms of percentages and were analyzed using the chi-squared test (with Fisher’s correction when necessary). The normal distribution of the variables was analyzed using the Kolmogorov-Smirnov test. The association of quantitative variables (hs-Tg and rhTSH-Tg) was calculated using Pearson’s linear correlation coefficient. A Receiving Operating Characteristics (ROC) curves analysis was performed to determine the accuracy of rhTSH-Tg and hs-Tg at 12 months after completing initial treatment, as a marker of long-term DTC status defining disease-free staging as an Excellent Response (ER) at DRS in the last monitoring visit. The area under the curve (AUC) and cut-off points for the highest sensitivity (Sens) and specificity (Sp) for both hs-Tg and rhTSH-Tg were analyzed. Finally, Sens, Sp, and predictive negative (NPV) and positive value (PPV) were evaluated for each cut-off points considering the existence or lack of ER at DRS in the last follow-up visit. Finally, differences between DRS according to initial hs-Tg or rhTSH-Tg levels compared to DRS at last follow-up visit were also evaluated. The accepted level of statistical significance was 5% (p < 0.05). The SPSS statistical software package, version 17.0 (SPSS Inc., Chicago, IL, United States), was used for analysis.

114 patients were evaluated (77% female) with a mean age at diagnosis of 46.4 ± 14.1 years and a mean follow-up of 7.9 ± 5.9 years since diagnosis. The mean tumor size was 1.8 ± 1.3 cm in diameter. The predominant histology found was papillary carcinoma (89.5%). The risk of recurrence at diagnosis were 61.1% and 13.9% for patients at low and high risk, respectively. (Table 1)

Table 1

Basal characteristics of patients with differentiated thyroid carcinoma.
BASAL CHARACTERISTICS	MEAN ± SD/ PERCENTAGE
Number of patients	114
Female (%)	77,2
Age at cancer Diagnosis (years)	46,4 ± 14,1
Years of evolution from the diagnosis to the last visit	7,9 ± 5,9
Size of main carcinoma (cm)	1,8 ± 1,3
Number of total I131 treatments (mCi)	1,4 ± 0,6
Total cumulative I131 dose (mCi)	153 ± 85,4
TYPE OF THYROID CANCER	%
Papillary	89,5
Classic	53,5
Follicular variant	28,9
Aggressive variants	7,1
Follicular	10,5
Oncocytic variant	58,1
Other variants	41,9
HISTOLOGICAL BASELINE CHARACTERISTICS	%
Multifocal	50,5
Capsular invasion	51,9
Vascular invasion	13,1
TUMOR STAGING	%
Stage I	82,9
Stage II	7,5
Stage III	8,6
Stage IV	1,0
RISK OF RECURRENCE	%
Low risk of recurrence	61,1
Medium risk of recurrence	25,0
High risk of recurrence	13,9

Table 2 shows baseline, intermediate (72 hours after the first rhTSH injection) and rhTSH-stimulated (3 days after the second rhTSH injection) TSH, free T4, Tg and AbTg levels assessed 12 months after completion of initial treatment (thyroidectomy and I131 ablation).

Table 2

Baseline, intermediate (72 hours after the first rhTSH injection) and rhTSH-stimulated (3 days after the second rhTSH injection) TSH, free T4, Thyroglobulin and Thyroglobulin antibodies levels assessed 12 months after completion of initial treatment (thyroidectomy and I131 ablation).
	BASELINE	INTERMEDIATE	rhTSH STIMULATED
TSH (mUI/L)	1.5 ± 1.2	151.4 ± 61.0	22.7 ± 16.4
Free T4 (ng/dl)	1.6 ± 0.3	1.6 ± 0.3	1.4 ± 0.6
Thyroglobulin (ng/ml)	0.4 ± 0.8	1.3 ± 3.0	2.1 ± 5.3
thyroglobulin antibodies (UI/ml)	11.0 ± 7.5	10.9 ± 7.4	11.6 ± 6.0

When assessing the correlation between rhTSH-Tg and baseline hs-Tg at 12 months after completion of initial treatment, a statistically significant strong positive lineal correlation was found r = 0.864, p < 0.001 (Fig. 1)

Receiving Operating Characteristics (ROC) curves analysis was performed to evaluate the accuracy of rhTSH-Tg and baseline hs-Tg at 12 months after completing initial treatment as a marker of long-term DTC status. We analyzed the overall performance of the initial assessment of Tg levels with respect to DRS at the last follow-up visit, defining disease-free as an Excellent Response (ER) at the last monitoring visit. The AUC showed good diagnostic accuracy for both baseline hs-Tg (AUC = 0.969; p < 0.001; 95% CI (0.941–0.997) and rhTSH-Tg (AUC = 0.944; p < 0.001; 95% CI (0.905–0.984). (Fig. 2a and 2b). However, hs-Tg AUC was significantly better than rhTSH-Tg AUC.

The highest S and Sp hs-Tg and rhTSH-Tg cutoff points were 0.110 ng/dl and 0.815 ng/dl, respectively (Fig. 2b). According to the ROC cutoff points, the diagnostic predictive values (S, Sp, NPV and PPV) of initial hs-Tg and rhTSH-Tg levels were evaluated with respect to the existence of ER in the DRS at the last follow-up attend. Hs-Tg cutoff point showed a S = 100%, Sp = 84.3%, NPV = 100% and a PPV = 70.5%. At the same time, rhTSH-Tg cutoff point showed a significantly worse diagnostic performance S = 96.8%, Sp = 84.3%, PPV = 69.7% and NPV = 98.6%

Initial DRS according to hs-Tg and rhTSH-Tg levels were evaluated compared to DRS at last follow-up visit.

In regard to the 83 patients with an ER at the last DTC assessment, 7,2% and 13,3% were incorrectly classified as Biochemical Incomplete Response (BIR) or Indeterminate Response (IR) according to initial hs-Tg and rhTSH-Tg DRS, respectively (p < 0.05). On the other hand, patients with BIR at final DRS assessment were more frequently classified as IR at initial evaluation with rhTSH-Tg (80%) than with hs-Tg (40%) (p < 0.05). Finally, patients with IR at final DRS assessment were more frequently misclassified as ER at initial evaluation with hs-Tg (20%) than with rhTSH-Tg (6.7%), (p < 0.05). (Table 3a and 3b)

Table 3a

Initial hs-Tg Dynamic Risk Stratification (DRS) compared to DRS at last follow-up visit.
		Last follow-up visit Dynamic Risk Stratification (DRS)
		Excellent response	Biochemical incomplete response	Structural incomplete response	Indeterminate response	Total
Initial baseline hs-Tg	Excellent response	77	1	0	3	81
	Biochemical incomplete response	1	8	1	1	11
	Indeterminate response	5	6	0	11	22
Total		83	15	1	15	114
Hs-Tg: High sensitive Thyroglobulin

Table 3b

Initial rhTSH-Tg Dynamic Risk Stratification (DRS) compared to DRS at last follow-up visit.
		Last follow-up visit Dynamic Risk Stratification (DRS)
		Excellent response	Biochemical incomplete response	Structural incomplete response	Indeterminate response	Total
Initial stimulated rhTSH-Tg	Excellent response	72	1	0	1	74
	Biochemical incomplete response	0	2	0	0	2
	Indeterminate response	11	12	1	14	38
Total		83	15	1	15	114
rhTSH-Tg: recombinant human TSG stimulated Thyroglobulin

Diagnostic, treatment, and follow-up DTC guidelines have recently evolved towards a less aggressive approach that ensures adequate monitoring, especially in less aggressive forms [2]. In fact, the definition of ER in DRS is based exclusively on the absence of imaging findings (mainly cervical ultrasound) and hs-Tg levels under levothyroxine suppressive treatment < 0.2 ng/mL or rhTSH-Tg < 1 ng/mL [2]. However, the absence of imaging finding but elevated Tg levels would classify these patients as IR (hs-Tg 0.2-1.0 ng/mL or rhTSH-Tg 1–10 ng/mL) or BIR (hs-Tg > 1.0 ng/mL or rhTSH-Tg > 10 ng/mL). Therefore, Tg is a key marker of recurrence or persistence disease in the long term evolution of DTC [11]. Nevertheless, these DRS cut-off points for Tg are arbitrary, mainly based on retrospective studies, and may be inconsistent when Tg is measured after stimulation (rhTSH-Tg) or under suppressive therapy (hs-Tg) for the same patient [7, 11].

The DRS allows reclassification of the DTC status throughout its evolution independently of its initial recurrence risk. Those with structural incomplete response (SIR) have the highest risk of morbidity and mortality in DTC. Hence the importance of Tg as a predictive marker of SIR [2].

During the last two decades, significant progress has been made in the measurement of hs-Tg. The hs-Tg assays have a 10-fold higher sensitivity than first-generation assays, which could theoretically obviate the need for Tg stimulation (either by thyroid hormone withdrawal or rhTSH) [12]. However, the implications of DRS reclassification by rhTSH-Tg levels are unclear, especially in those patients with BIR and IR [13, 14].

In the present study we evaluated both questions: 1) the long-term predictive value of hs-Tg and rhTSH-Tg 12 months after completion of initial treatment (total thyroidectomy and I131 ablation) in a cohort with mean follow-up of 7.9 years; and 2) the divergences in DRS according to hs-Tg or rhTSH-Tg levels and their implications on the follow-up.

In the present article, the predictive value of ER at the last follow-up visit for Tg levels 12 months after completing initial treatment showed a high NPV. In fact, a hs-Tg cutoff point of 0.110 ng/mL showed a NPV of 100%. That is, all patients with an undetectable hs-Tg level under levothyroxine treatment 12 months after completing treatment with total thyroidectomy and I131 ablation remained in ER throughout follow-up. These results agree with those previously published in which the NPV is estimated to be around 97–99%. Thus, the risk of a false negative at undetectable hs-Tg levels would be no more than 1% [7, 11].

Surprisingly, the results obtained for rhTSH-Tg did not improve the overall test performance with respect to the disease status at the last follow-up visit. In fact, for a rhTSH-Tg cutoff point of 0.815 ng/dl the NPV and PPV of the test worsened slightly with respect to the predictive ability of hs-Tg. These worse results were due to a single 44-year-old female patient with follicular variant CDT and IR after a follow-up longer than 9 years (last follow-up visit hs-Tg = 0.22 ng/dl) and rhTSH-Tg from 0.19 to 0.37 ng/dl. Despite the borderline positivity in hs-Tg levels, it did not reach the cut-off point established by International Guidelines for rhTSH-Tg DRS, not even the one with the highest sensitivity/specificity calculated for the present study. Although it is true that the risk of developing Structural Disease in this patient is very low, it is undeniable to recognize that the cut-off points established for the definition of the DRS are arbitrary and may even cause divergences in DRS classification depending on whether rhTSH-Tg or hs-Tg is assessed, even though there is a clear correlation between both values (Fig. 1). In any case, our results support the inefficacy of rhTSH-Tg in predicting long-term response to DTC, making this costly procedure unnecessary, with a negative impact on patients´ quality of life, especially in those with an ER after completing initial treatment (certainly the most common subgroup in CDT) [11, 15, 16].

At the same time, special attention should be paid to the lower PPV independent of the type of Tg measurement. Tg levels 12 months after completing initial treatment are not exempt from the risk of false positive results. In fact, 15.7% of patients identified as ER at the end of follow-up were classified as (false) positives in the initial assessment. The persistence of healthy thyroid tissue due to the temporal proximity of the I131 ablative dose, the greater sensitivity of ultrasensitive tests, and even the evolution towards spontaneous resolution in a high proportion of DTC could explain this fact [17]. In any case, our results are similar and even slightly superior to those previously described [11]. It supports the usefulness of hs-Tg as a discrimination tool for those patients with initial ER whose frequency and intensity of follow-up could be reduced, with the consequent cost savings, optimization of resources and reduction of patient anxiety during follow-up [18]

Finally, the DRS assess the risk of recurrence at any time during the DTC evolution in relation to the treatment response (ATA2015). In this sense, those patients without structural disease by imaging will define their DRS, and therefore the risk of recurrence, exclusively based on Tg levels [4, 5]. These Tg cut-off points are arbitrary, based on retrospective studies, and may differ depending on whether they are classified by hs-Tg or rhTSH-Tg [11].

In the present study, DRS classification using rhTSH-Tg 12 months after completing initial treatment overestimated by more than twofold the number of patients initially identified as IR in both ER and BIR groups at the last follow-up visit. However, it provided a slightly better predictive value in those patients with an initial IR using rhTSH-Tg (93.3%) than hs-Tg (73.3%). Despite these apparent discrepancies between DRS classifications, the risk of recurrence associated with BIR or IR remains nowadays a subject of debate and depends on numerous variables (progressive increase in Tg levels, doubling time, etc.) and may evolve towards spontaneous resolution without further treatment in a large number of patients [17, 19]. Moreover, as shown in Table 3, 13.3% of patients with IR by rhTSH-Tg spontaneously progress to ER during follow-up. In fact, the clinical relevance of detectable but only slightly elevated hs-Tg levels is still unclear.

Although there is a recent study aimed at evaluating the usefulness of rhTSH-Tg 5 years after completion of initial treatment to reclassify DRS in those cases with IR or BIR [14], a regular hs-Tg monitoring strategy would probably have a similar result with a lower cost and patients´ anxiety due to the overall good prognosis [20].

The present study has certain limitations to be considered. First, classic studies attribute to DTC the risk of recurrence even several decades after diagnosis [21], which would reduce the predictive value of hs-Tg after completing the initial treatment even in a cohort with an average follow-up of almost 8 years. However, more recent studies show that more than 80% of recurrences are identified in the first 5 years [22], which would support the clinical relevance of our results. This improvement in the early detection of recurrences is essentially due to the technical improvement on cervical ultrasound imaging and hs-Tg during the last decade. In this sense, the high NPV of undetectable hs-Tg and the absence findings on imaging evaluation, added to the higher risk of recurrence within the first 5 years might support the possibility of extending follow-up and even definitively discharging those patients with low-risk DTC after this period [18]. Finally, the smaller number of patients with IR/BIR compared to those with ER could reduce the statistical significance in those patients, however the prospective and longitudinal design of the present study as well as the similarity with other current cohorts ensure its representativeness and reflect the reality of DTC follow-up [23].

In conclusion, in those patients with ER 12 months after completing initial treatment (total thyroidectomy and I131 ablative treatment) the rhTSH-Tg did not provide relevant information. An ER after initial treatment was associated with a high NPV. In those patients with IR or BIR, rhTSH-Tg identified a greater number of patients with IR, with no apparent practical implication during follow-up.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

The authors have no relevant financial or non-financial interests to disclose.

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Gonzalo Díaz Soto and Pablo Fernandez Velasco. The first draft of the manuscript was written by Pablo Fernandez Velasco and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hospital Universitario de Valladolid Spain

Informed consent was obtained from all individual participants included in the study

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Predictive Value and Dynamic Risk Stratification of High Sensitive Basal or Stimulated Thyroglobulin Assay in a Long-term Thyroid Carcinoma Cohort

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