Accuracy of Stimulated Thyroglobulin Level in Guiding Follow-up of Patients with Differentiated Thyroid Carcinoma without Elevated Antithyroglobulin Antibodies

INTRODUCTION

Differentiated thyroid cancer (DTC) is among the most common endocrine cancers globally, and the 10th most common cancer worldwide.^[1] DTC mainly includes papillary and follicular thyroid cancers. These are generally slow-growing and have a good prognosis with early diagnosis and prompt treatment. The mainstay of initial treatment is surgical resection, most commonly total or near-total thyroidectomy. The role of the nuclear medicine physician becomes pivotal in the postoperative phase, encompassing radioactive iodine (RAI) therapy, risk-adapted follow-up, and surveillance imaging. The American Thyroid Association (ATA) recommends a postoperative risk stratification system to guide subsequent management and optimize individualized patient care.^[2]

Serum thyroglobulin (Tg) is a well-established tumor marker of DTC and plays a pivotal role in postoperative and post-RAI surveillance, as well as the detection of recurrence.^[3] Various international guidelines, such as those from the European Society of Medical Oncology and the ATA, recommend using serum Tg to guide the management of patients with thyroid cancer. Stimulated Tg (sTg) refers to the serum Tg concentration measured after thyroid-stimulating hormone (TSH) stimulation, either through thyroid hormone withdrawal or administration of recombinant human TSH). The elevation of TSH enhances Tg production and release from residual normal thyroid tissue or DTC cells, thereby increasing the sensitivity of Tg measurement for detecting residual or recurrent disease. sTg has emerged as an essential biomarker for risk-adapted follow-up across all ATA-defined risk categories.^[3] An excellent response following RAI therapy is typically characterized by an sTg level below 1 ng/mL in the absence of elevated anti-TgAb.^[4] ATA recommends performing a diagnostic whole-body iodine scan (WBIS) approximately 6 months after initial therapy in patients with intermediate- and high-risk DTC, a practice widely adopted in most of the centers worldwide.^[2] However, several studies have demonstrated that Tg levels exhibit high sensitivity for detecting recurrent or residual disease, suggesting that routine follow-up diagnostic WBIS may be unnecessary in selected patients.^[3,5-7] This study is designed to evaluate the role of sTg in the follow-up of patients with DTC at 6 months after RAI therapy, with particular emphasis on its predictive value and potential to optimize management across all ATA risk categories – low, intermediate, and high risk. The study aims to determine whether a follow-up diagnostic WBIS, performed 6 months after RAI therapy, can be safely omitted in patients demonstrating a sTg level of ≤1 ng/mL across all ATA risk groups.

MATERIAL AND METHODS

This single-center, retrospective study was conducted at a tertiary care hospital in India and included patients between June 2020 and November 2024. Eligible patients were male and female patients, ≥18 years of age at the time of diagnosis, who underwent total thyroidectomy with or without neck dissection and had histopathologically evidence of DTC. Inclusion criteria required the availability of sTg levels and WBIS, both postsurgery (before RAI therapy) and at the 6-month follow-up post-RAI therapy. Patients with incomplete histopathology reports or elevated TgAb levels at any stage of treatment and follow-up were excluded from the study.

A total of 530 patients with DTC who had undergone surgery and RAI therapy were on follow-up. Of these, 390 patients met the eligibility criteria and were included in the final analysis. Exclusions comprised 48 patients with elevated TgAb levels, 52 patients with incomplete or inadequate histopathology reports from outside institutions, and 40 patients under 18 years of age. The findings of sTg levels and WBIS findings at 6 months post-RAI therapy were analyzed across all three ATA risk categories.

All patients underwent a diagnostic WBIS following surgery, followed by RAI therapy within 1 week. A repeat diagnostic WBIS was performed 6 months post-RAI treatment. Before each WBIS, patients discontinued thyroxine and adhered to a low-iodine diet, avoiding iodinated contrast studies and medications for 3–4 weeks. At the end of this period, sTg and TgAb levels were measured. Patients achieving a serum TSH level >30 mIU/L received 1–3 mCi of RAI (¹³¹I) orally. Imaging was performed 48 h later using a GE Discovery NM/CT 670 gamma camera equipped with high-energy general-purpose collimators and a 20% energy window centered at 364 keV. Scans were interpreted by an experienced nuclear medicine physician. On the other hand, sTg levels were quantified using a chemiluminescence immunoassay method.

A positive WBIS was defined as the presence of one or more foci of abnormal RAI uptake outside the expected physiological sites. Abnormal uptake sites included residual thyroid tissue or metastatic locations such as cervical or mediastinal lymph nodes, lungs, and bones. Single-photon emission computed tomography (CT)/CT was performed to anatomically localize abnormal foci identified on planar imaging. Histopathological evaluation was undertaken for suspicious cervical lymph nodes to confirm metastatic involvement. Lung and bone lesions were monitored by serial imaging and response to further treatment in correlation to sTg levels to confirm them as disease involvement.

RESULTS

DISCUSSION

This study investigated the utility of follow-up sTg levels in guiding the role of diagnostic WBIS in patients with DTC across all ATA risk categories. sTg level of ≤1 ng/mL at the first follow-up (6 months postinitial therapy) demonstrated a 100% NPV for a positive WBIS across low, intermediate, and high-risk DTC patients with negative TgAb levels. This suggests that routine follow-up WBIS may be safely omitted in such patients, potentially streamlining patient management, reducing radiation exposure, and lowering healthcare costs.

The cohort predominantly comprised females and patients with PTC, which aligns with the known epidemiology of DTC.^[8] The stratification by ATA risk categories showed a significant proportion of patients in the intermediate-risk group, reflecting a common distribution in tertiary care centers.^[9]

In our investigation, individuals exhibiting sTg levels of 1 ng/mL or below, encompassing 17 patients categorized as high-risk according to the ATA classification, demonstrated a negative WBIS. This represents a significant clinical observation, as prevailing guidelines generally recommend routine WBIS for patients classified as intermediate risk and high risk. This study findings indicate that a substantial proportion of patients with sTg ≤1 ng/mL (58.2% of the total patient cohort) could have avoided WBIS without compromising diagnostic accuracy, based solely on a clearly defined sTg biomarker threshold. The identification of this distinct patient subgroup is of paramount importance.

Conversely, all 14 patients (3.6% of the total cohort) who had a positive WBIS at follow-up had sTg levels >1 ng/mL. Within this sTg >1 ng/mL group, the likelihood of a positive WBIS increased with the ATA risk category: 0% in low-risk, 2.5% in intermediate-risk, and notably 23.4% in high-risk patients. This highlights the importance of integrating sTg levels with ATA risk stratification for decision-making when sTg is above the 1 ng/mL threshold.

The diagnostic performance metrics derived (sensitivity 100%, specificity 43.35%, PPV 6.17%, NPV 100% for sTg >1 ng/mL predicting positive WBIS) emphasize the strength of a low sTg in ruling out disease. A low sTg value reliably excludes disease, allowing clinicians to safely omit WBIS. The relatively low specificity and PPV for sTg >1 ng/mL indicate that many patients with sTg >1 ng/mL will still have a negative WBIS, particularly in lower-risk groups. The low PPV simply means that an sTg >1 ng/mL is not, by itself, a good confirmation of disease, which is why those patients (especially high-risk) still require further evaluation. This is consistent with the understanding that sTg can be elevated due to benign remnants or microscopic disease, not always visualized on WBIS.

The findings of this study, conducted in an Indian population, align with and expand on previous international research suggesting that low sTg levels can obviate the need for routine diagnostic WBIS. These findings are further supported by previous studies, such as Jeon and Jung, who performed a study on 438 patients of DTC in low risk and intermediate risk and concluded that diagnostic WBIS after RAI ablation in intermediate-risk patients with DTC may not be necessary if sTg <2 ng/mL.^[10] Similarly, Pacini et al.’s study in 315 patients concluded that diagnostic scans could be avoided in patients with undetectable levels of sTg.^[7] Barres et al.’s study done in 1093 patients of DTC found that sTg <1 ng/mL at 6–12 months predicted long-term remission with >95% NPV, even in advanced-stage disease.^[11] Similarly, Jammah et al. showed that 98% of patients with sTg <1 ng/mL remained disease-free, confirming the redundancy of routine stimulated testing in Tg-negative patients.^[12] None of these studies stratified patients by risk category according to the ATA, which is essential in the management of patients.

Our study findings align with the updated ATA 2025 guidelines, which advise against routine diagnostic WBIS in low- and intermediate-risk patients showing an “excellent response.” Collectively, these international studies and updated ATA recommendations support the present study’s conclusion that follow-up WBIS can be safely omitted in patients with sTg ≤1 ng/mL and negative TgAb levels, validating a cost-effective, evidence-based, and patient-centric strategy for DTC surveillance.^[2]

The observation that no recurrences occurred in patients with a negative follow-up WBIS during the median follow-up of 28 months is reassuring, although longer follow-up is generally required in DTC to definitively assess long-term recurrence rates.

Literature at present shows a lacuna of data regarding the Indian population, which contributes to a major part of the world population. We attempted to establish the threshold levels of sTg in the Indian population below which WBIS could be avoided across all ATA risk categories. This approach helps to reduce the cost and radiation exposure associated with WBIS. Unlike many previous studies that focused only on low- or intermediate-risk patients, our study explicitly included high-risk patients and found the 100% NPV for sTg ≤1 ng/mL held true even in this group (n = 17). Our findings provide timely, real-world evidence supporting the new 2025 ATA guidelines’ recommendation to move away from routine diagnostic WBIS.

This study has a few limitations. First, its retrospective nature may introduce selection bias and reliance on previously recorded data. Further, the number of patients in the high-risk category with sTg ≤1 ng/mL was relatively small (n = 17), and while all had negative WBIS, larger numbers would provide greater confidence for this specific subgroup. Similarly, the overall number of positive WBIS findings was limited (n = 14), which can affect the stability of diagnostic accuracy estimates, particularly PPV. The median follow-up duration of 28 months is adequate for assessing early response but may not be sufficient to capture all late recurrences characteristic of DTC. The study focused on sTg; however, the role of unstimulated Tg trends or neck ultrasound findings in conjunction with sTg was not evaluated.

CONCLUSION

Serum sTg level ≤1 ng/mL with normal serum TgAb levels at follow-up 6-month postradioiodine therapy precisely rules out residual or recurrent disease across all ATA risk categories. Routine follow-up WBIS may be safely omitted in this group of patients, enabling more cost-effective and patient-centric follow-up. Larger prospective studies with longer follow-up are warranted to validate these findings and refine follow-up protocols.