What is the clinical significance of a PIK3CA (Phosphatidylinositol 3-kinase, catalytic, alpha polypeptide) mutation in a Bethesda III thyroid nodule?

PIK3CA Mutations in Bethesda III Thyroid Nodules: Clinical Significance and Management

PIK3CA mutation testing in Bethesda III thyroid nodules can assist in risk stratification for malignancy and should be considered as part of a molecular testing panel to guide management decisions, particularly when other diagnostic approaches are inconclusive.

Understanding Bethesda III Thyroid Nodules

Bethesda III category, also known as Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance (AUS/FLUS), represents one of the most challenging diagnostic categories in thyroid cytopathology:

• Bethesda III nodules have an estimated malignancy risk of 10-30% according to most studies 1, 2
• Some specialized cancer centers report even higher malignancy rates of 26.6-37.8% 3
• Repeat FNA for Bethesda III nodules that yield a second Bethesda III result may have an even higher malignancy risk (73.1%) 4

Role of PIK3CA Mutations in Thyroid Nodules

PIK3CA (Phosphatidylinositol 3-kinase, catalytic, alpha polypeptide) mutations have emerging significance in thyroid nodule evaluation:

1. Diagnostic Value:

   • PIK3CA mutations can assist in the diagnosis of benign and malignant cancer subtypes and provide prognostic information 5
   • According to the 2025 Chinese guidelines for ultrasound-guided thermal ablation of thyroid nodules, PIK3CA gene testing can be used alongside BRAF/RAS, TERT, and TP53 testing to improve diagnostic accuracy 5

2. Prevalence in Thyroid Nodules:

   • PIK3CA mutations are less common than other mutations in thyroid nodules, occurring in less than 1% of tested nodules 6
   • They are more frequently found in poorly differentiated and anaplastic thyroid carcinomas, often co-occurring with other genomic alterations 5

3. Association with Aggressive Disease:

   • PIK3CA mutations, particularly when co-occurring with other mutations (TERT promoter, TP53), are associated with more aggressive thyroid cancer variants 5
   • The WHO classification identifies PIK3CA as one of the molecular markers associated with poorly differentiated carcinoma 5

Clinical Approach to Bethesda III Nodules with PIK3CA Mutations

Initial Evaluation

1. Comprehensive Molecular Testing:

   • For Bethesda III nodules, molecular testing including PIK3CA, BRAF, RAS, TERT, and TP53 should be performed to improve risk stratification 5
   • Combined mutation analysis with microRNA classification can significantly improve risk stratification of indeterminate thyroid nodules 6

2. Ultrasound Correlation:

   • Correlate molecular findings with ultrasound characteristics using TI-RADS classification 7
   • High-risk ultrasound features (solid consistency, irregular/microlobulated margins, nonparallel shape) in combination with PIK3CA mutations further increase malignancy risk 4

Management Algorithm

1. For Bethesda III nodules with PIK3CA mutation alone:

   • Consider surgical management, especially if other high-risk features are present
   • The presence of PIK3CA mutation increases the baseline risk of malignancy in Bethesda III nodules

2. For Bethesda III nodules with PIK3CA mutation plus other mutations:

   • When PIK3CA mutations co-occur with TERT promoter, TP53, or BRAF mutations, surgical management is strongly recommended due to significantly increased malignancy risk 5
   • These combinations are associated with more aggressive disease behavior

3. For Bethesda III nodules with PIK3CA mutation and high-risk ultrasound features:

   • Surgical management is recommended rather than repeat FNA 4
   • Irregular/microlobulated margins on ultrasound combined with molecular alterations are particularly concerning (odds ratio = 15.576) 4

Pitfalls and Considerations

1. Limitations of Molecular Testing:

   • PIK3CA mutation alone has limited predictive value and should be interpreted in context with other molecular and clinical findings 6
   • False positives and false negatives can occur with any molecular testing approach

2. Institutional Variation:

   • Malignancy rates for Bethesda III nodules vary significantly between institutions 3
   • Cancer centers tend to report higher malignancy rates than community settings

3. Follow-up Considerations:

   • For patients who do not undergo immediate surgery, close surveillance with repeat ultrasound at 6-12 months is essential 7
   • Consider repeat FNA with molecular testing if ultrasound features change

Conclusion

PIK3CA mutations in Bethesda III thyroid nodules represent an important molecular marker that can help guide clinical decision-making. While less common than other mutations, their presence, particularly when combined with other genomic alterations or suspicious ultrasound features, increases the risk of malignancy and may warrant more aggressive management. A comprehensive approach incorporating cytology, molecular testing, and imaging characteristics provides the most accurate risk assessment for these challenging nodules.