Highlight
• The standard AJCC classification for papillary thyroid cancer (PTC) relies solely on clinical parameters and shows limited accuracy in mortality risk prediction.
• This international, multicentre study involving 4746 patients demonstrates that adding BRAFV600E and TERT promoter mutation status significantly refines risk stratification and mortality prediction.
• Dual mutation of BRAFV600E and TERTp substantially increases mortality risk across AJCC stages, influencing survival estimates especially in early stage disease.
• Incorporation of genetic data into AJCC improves prognostic precision, potentially guiding more personalized clinical management for PTC patients.
Study Background
Papillary thyroid cancer is the most common thyroid malignancy, generally associated with excellent prognosis. However, subsets of patients experience disease recurrence and cancer-specific mortality. The American Joint Committee on Cancer (AJCC) staging system, used worldwide for risk stratification, is primarily based on tumor size, nodal involvement, metastasis, and patient age. Despite multiple revisions culminating in the 8th edition, the AJCC system’s predictive accuracy, particularly for mortality, remains suboptimal, partly due to ignoring molecular tumor characteristics.
Advances in molecular oncology have identified recurrent mutations in BRAF (particularly BRAFV600E) and TERT promoter (TERTp) in papillary thyroid cancers. BRAFV600E mutation drives MAPK pathway activation, while TERTp mutations are linked to telomerase reactivation and aggressive tumor behavior. Recent data suggest these genetic alterations are associated with poorer outcomes, but their integration into clinical prognostic models has been limited.
This study addresses the unmet clinical need for improved risk assessment by integrating BRAF and TERTp mutation statuses into the AJCC staging framework to refine prediction of PTC-specific mortality.
Study Design
This retrospective cohort study encompassed 4746 patients with histologically confirmed papillary thyroid cancer treated surgically (total or hemithyroidectomy, with or without neck dissection) across 15 centers from 10 countries spanning Asia, Europe, and the Americas. Patient data span from 1979 to 2023, representing diverse ethnicities and both adult and pediatric populations (89 patients ≤18 years). Postoperative treatment uniformly included radioiodine ablation and thyroid-stimulating hormone level optimization.
Genomic DNA isolated from either surgical or cytological specimens was analyzed for the presence of BRAFV600E and TERTp mutations at each center. Staging was reassessed using the 7th and 8th editions of the AJCC system (AJCC7E and AJCC8E). Outcomes focused on papillary thyroid cancer-specific mortality, expressed as mortality rates per 1000 person-years and hazard ratios (HR) comparing genetically defined subgroups across clinical stages.
Key Findings
The cohort had a median age of 48 years, with a female predominance (76.1%) and balanced ethnic representation (48.6% Asian, 47.6% White). Major findings are summarized as follows:
- AJCC7E Staging: Patients harboring both BRAFV600E and TERTp mutations (“dual mutations”) exhibited markedly increased mortality risks across all AJCC stages compared to wildtype counterparts. HRs were notably elevated in stages II (HR 5.94, p=0.015) and III (HR 4.04, p=0.00037), with stage I trending higher though not statistically significant (HR 5.96, p=0.10). TERTp mutation alone significantly increased mortality risk in stage IV disease (HR 3.57, p<0.0001).
- AJCC8E Staging: Integration of dual mutations also showed significantly increased mortality in stages I (adjusted HR 10.30, p<0.0001) and II (HR 3.95, p=0.00020). Stage III showed an increased trend not reaching statistical significance (HR 1.77, p=0.072). In contrast to AJCC7E, the dual mutations did not confer increased mortality risk in stage IV disease (HR 0.95, p=0.89), though TERTp mutation alone significantly elevated mortality risk (HR 2.75, p=0.0049).
- Wildtype Patients: Those without BRAFV600E or TERTp mutations had notably flat survival curves, particularly for AJCC7E stages I-III and AJCC8E stages I-II, underscoring the indolent nature of genetically wildtype tumors.
These data underscore how genetic profiling substantially alters mortality risk estimations within each AJCC stage, notably upgrading risk for patients previously categorized as low or intermediate risk.
Expert Commentary
The study represents a critical step in precision oncology for papillary thyroid cancer by systematically validating the prognostic value of combining BRAF and TERT promoter mutations alongside established clinical staging. Integrating molecular markers addresses key limitations of the AJCC system’s clinical-only approach, reconciling observed heterogeneity in outcomes among patients sharing similar clinical stages.
The differential impact of the dual mutation in early-stage disease highlights that molecular factors can uncover aggressive biology obscured by traditional metrics. Conversely, the increased mortality risk associated with TERTp mutations in advanced stage disease emphasizes its role as a high-risk genetic driver.
Limitations include the retrospective design and potential variability in mutation testing methods across centers. Also, the dual mutation’s lack of impact on stage IV mortality in AJCC8E suggests further refinement of molecular risk models is necessary, possibly incorporating additional biomarkers or clinical factors. Nonetheless, the study’s large, ethnically diverse international cohort enhances generalizability.
These findings align with emerging guidelines that advocate for molecular testing in thyroid cancer prognostication. Clinical adoption could enable tailored surveillance intensity and therapeutic strategies, such as selective use of adjuvant therapies or enrollment in clinical trials targeting molecular pathways.
Conclusion
Incorporating BRAFV600E and TERT promoter mutation status into the AJCC classification profoundly improves mortality risk stratification in papillary thyroid cancer. This genetic augmentation of traditional clinical staging reveals high-risk subgroups within otherwise favorable AJCC stages, refining prognosis and informing personalized management.
Future prospective studies and integration of additional genomic and epigenomic markers may further optimize the risk classification system. Ultimately, combining molecular and clinical data represents the evolving paradigm in oncology staging, promising enhanced prognostication and individualized care in thyroid cancer.
Funding and Clinical Trials
This research was supported by multiple international funding sources including the National Institute on Aging, NIH, American Association for Cancer Research, and various governmental health agencies across the Czech Republic, Portugal, Italy, Japan, Colombia, Poland, Indonesia, and Korea.
References
Xing M, Lin S, Mathur A, et al. Genetic modification of the AJCC classification of papillary thyroid cancer: an international, multicentre, retrospective cohort study. Lancet Oncol. 2025 Oct;26(10):1382-1392.
