New nomogram predicts five-year progression risk in thyroid cancer with lung metastases

Researchers in China have built and tested a statistical tool that estimates the probability that a patient with differentiated thyroid cancer and lung metastases will remain free of disease progression for five years after initial radioiodine therapy. The tool, a nomogram, combines four pieces of information that are routinely available in clinical practice: the patient’s age at diagnosis, the size of the primary tumor, the level of pre-ablation stimulated thyroglobulin in the blood, and whether the lung metastases took up radioiodine on the first post-treatment scan. The study, published in Frontiers in Endocrinology, was a retrospective analysis of medical records from 284 patients treated at two hospitals, and its authors describe the model as a preliminary risk-stratification instrument that still requires prospective, multicenter validation.

Differentiated thyroid cancer, which includes papillary and follicular subtypes, accounts for more than 90 percent of all thyroid cancers and generally carries a favorable outlook, with 10-year survival rates exceeding 90 percent after total thyroidectomy, selective radioiodine therapy and thyroid-stimulating hormone suppression. The picture changes substantially when the disease spreads to the lungs. According to the background cited in the paper, roughly 4 to 23 percent of differentiated thyroid cancer patients develop distant metastases during the course of their disease, and the lungs are the most frequently involved site. For patients with lung metastases, 10-year survival rates range from approximately 60 to 88 percent depending on clinical and treatment-related factors.

A further concern is the tendency of lung-metastatic disease to stop responding to radioiodine. The authors note that approximately two-thirds of these patients may eventually progress to radioiodine-refractory disease, a stage at which the 10-year survival rate falls below 10 percent. Once tumors lose the ability to concentrate iodine, repeated radioiodine treatments offer limited benefit while carrying the risk of adverse effects, and clinicians may need to consider alternatives such as multi-kinase inhibitors. Identifying which patients are likely to progress early, rather than waiting for changes to appear on serial imaging, is therefore a central goal in managing this population, and the study was designed to address that need.

The research team, led by investigators at the Affiliated Hospital of Qingdao University with collaborators at Shanghai Tenth People’s Hospital, assembled two cohorts from patients treated between January 2006 and December 2024 in Qingdao and between January 2016 and December 2020 in Shanghai. All patients had undergone total or subtotal thyroidectomy followed by at least one course of radioiodine therapy, had histopathologically confirmed differentiated thyroid cancer, and were at least 18 years old at diagnosis. Patients with positive anti-thyroglobulin antibodies, concurrent malignancies, missing data or other anti-tumor therapies were excluded. The Qingdao group of 184 patients served as the training cohort, while the Shanghai group of 100 patients served as an external validation cohort.

Progressive disease was defined using the Response Evaluation Criteria in Solid Tumors version 1.1, applied to imaging reviewed every 6 to 12 months after radioiodine therapy by two blinded, board-certified nuclear medicine physicians, with disagreements resolved by consensus or a third senior reviewer. For patients with measurable lesions of at least 10 millimeters, progression meant a 20 percent or greater increase in the sum of the longest diameters with an absolute increase of at least 5 millimeters, or the appearance of new lesions. Serum thyroglobulin was used only as supportive biochemical information and did not independently define structural progression. At the final follow-up, 25.0 percent of the training cohort and 33.0 percent of the validation cohort had experienced progressive disease, a difference the authors report as not statistically significant.

A key input to the model was pre-ablation stimulated thyroglobulin, measured in blood samples collected before the first radioiodine treatment after thyroid hormone withdrawal. In the training cohort, the median level among patients who later progressed was 1017.5 nanograms per milliliter, compared with 87.0 nanograms per milliliter among those who did not, a difference the authors report as highly significant. Receiver operating characteristic analysis identified an optimal cutoff of 528.5 nanograms per milliliter, which yielded a sensitivity of 69.6 percent, a specificity of 87.7 percent, and an area under the curve of 0.823 for predicting progression in that cohort.

Using univariable and multivariable Cox proportional hazards regression, the team identified four independent predictors of progression in the training cohort. Age at diagnosis of 55 years or older carried a hazard ratio of 3.374 compared with younger patients, and the authors note that this threshold matches the stratification point adopted in the eighth edition of the AJCC TNM staging system. Each additional centimeter of primary tumor size raised the hazard by a factor of 1.264. A pre-ablation stimulated thyroglobulin level at or above 528.5 nanograms per milliliter carried a hazard ratio of 2.709. The strongest predictor was initial radioiodine avidity status: patients whose lung metastases showed partial or no uptake on the post-therapeutic scan had a hazard ratio of 8.462 relative to those with avid lesions.

The nomogram assigns points to each of the four variables and sums them to produce an estimated five-year progression-free survival probability, intended for use immediately after the first post-therapy scan, when all four inputs are available. Of the four predictors, initial radioiodine avidity status contributed the most to the score, followed by tumor size, thyroglobulin level and age. The authors link the avidity finding to tumor dedifferentiation, a process involving downregulation of the sodium-iodide symporter that is critical for iodine uptake, and they cite prior work reporting that loss of iodine avidity was the strongest independent predictor of poor prognosis in papillary thyroid cancer patients with lung metastases.

Performance testing produced a C-index of 0.874 in the training cohort and 0.769 in the external validation cohort, with time-dependent ROC areas under the curve of 0.897 and 0.800 respectively. Calibration curves showed close agreement between predicted probabilities and observed event rates in both cohorts, and decision curve analysis indicated favorable clinical net benefit across threshold probabilities. The authors argue that, unlike the AJCC/TNM system, which primarily predicts disease-specific mortality, their tool provides an individualized quantitative estimate of progression-free survival using parameters available in routine practice, which may be particularly useful in settings where expensive molecular imaging such as 18F-FDG PET/CT is not universally accessible.

The study’s authors are explicit about its limitations. The retrospective design carries inherent selection bias, the external validation cohort came from a single center, and the thyroglobulin cutoff was derived from the same training cohort used to build the model, which may introduce optimism. Genetic markers such as TERT promoter mutations were not included, and follow-up duration varied across patients, so the five-year prediction should be interpreted cautiously in patients with shorter observation periods. The team concludes that older age, larger tumor size, partial or absent radioiodine avidity, and elevated pre-ablation stimulated thyroglobulin are independent predictors of progression in this population, and that the resulting nomogram should be regarded as a preliminary risk-stratification tool pending further prospective multicenter validation.

Subject of Research: A nomogram predicting five-year progression-free survival in differentiated thyroid cancer patients with lung metastases

Article Title: Development and validation of a nomogram for predicting 5-year progression-free survival probability in differentiated thyroid cancer patients with lung metastases

Article References: Wang, C., Zhang, X., Zhang, Y., Liu, J., Qin, G., Han, P., Li, Y., Wang, R., & Wang, X. (2026). Development and validation of a nomogram for predicting 5-year progression-free survival probability in differentiated thyroid cancer patients with lung metastases. Frontiers in Endocrinology, 17, Article 1938835. https://doi.org/10.3389/fendo.2026.1938835

Image Credits: AI Generated

DOI: 10.3389/fendo.2026.1938835

Keywords: differentiated thyroid cancer, lung metastases, nomogram, progression-free survival, progressive disease, radioiodine therapy, thyroglobulin, RAI avidity, risk stratification, Cox regression, retrospective study, external validation