Is a wait and see approach with monitoring appropriate for a patient with thyroid nodules, normal thyroid function, and an NRAS (neuroblastoma RAS viral oncogene homolog) p.Q61K mutation?

Management of Thyroid Nodules with NRAS Q61K Mutation

Surgery is recommended for this patient with a 3.07 cm TR4 thyroid nodule with atypia of undetermined significance, Hurthle cells, and NRAS p.Q61K mutation, rather than a wait-and-see approach, due to the intermediate-to-high probability of cancer.

Evaluation of the Current Case

• The patient has a 3.07 cm right thyroid nodule classified as TR4 (intermediate suspicion) with atypia of undetermined significance (AUS) on cytology and NRAS p.Q61K mutation at 13% allele frequency 1
• The molecular testing indicates an intermediate-to-high probability of cancer or NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) 1
• The left thyroid nodule is smaller (1.0-1.2 cm), also TR4, but with benign cytology (Bethesda II) 1
• Thyroid function tests are normal, and autoimmune thyroiditis (Hashimoto's) is present 1

Significance of NRAS Mutation

• NRAS mutations, particularly at codon 61 (including Q61K), are associated with follicular-patterned thyroid neoplasms 2
• The presence of an NRAS mutation in a follicular neoplasm increases the risk of malignancy, with studies showing a positive predictive value of 67% for cancer 3
• While NRAS Q61K mutations are less common than NRAS Q61R (15% vs. 44% of RAS mutations), they still indicate increased risk of neoplasia 2
• NRAS-mutated nodules are associated with a higher overall malignancy rate (79% versus 52% in NRAS-negative nodules) 3

Risk Assessment and Management Options

• The 3.07 cm size of the nodule exceeds the threshold for observation, as most guidelines do not recommend observation for nodules >1 cm with suspicious features 1
• The combination of NRAS mutation, follicular/Hurthle-cell cytology, and nodule size indicates a significant risk of follicular carcinoma, Hurthle cell carcinoma, or NIFTP 1
• While NIFTP is considered a low-risk lesion with excellent prognosis (<1% risk of recurrence), it requires complete histopathological examination to confirm the diagnosis, which necessitates surgical excision 1
• The patient also has Hashimoto's thyroiditis, which contributes to the Hurthle cell changes but does not negate the risk associated with the NRAS mutation 4

Recommendations Based on Current Guidelines

• For nodules with indeterminate cytology (AUS) and molecular testing suggesting increased cancer risk, surgical management is recommended rather than observation 1
• The size of the nodule (3.07 cm) exceeds the threshold where active surveillance would typically be considered, even for low-risk lesions 1
• While thermal ablation may be considered for some thyroid nodules, it is primarily recommended for smaller, well-characterized lesions or when surgery is contraindicated 1
• Regular follow-up is essential regardless of the treatment approach, including assessment of nodule volume, clinical symptoms, and thyroid function 1

Why Surgery is Preferred Over Observation

• The nodule's size (3.07 cm) is significant and exceeds thresholds for observation in most guidelines 1
• The presence of an NRAS mutation increases the likelihood of malignancy, particularly follicular-patterned carcinomas 3, 4
• Complete histopathological examination is necessary to determine if the lesion is NIFTP, minimally invasive follicular carcinoma, or another entity 1
• Surgical management allows for definitive diagnosis and appropriate risk stratification for any potential malignancy 1
• Even if the final diagnosis is NIFTP, surgical excision is necessary to confirm this diagnosis through thorough examination of the capsule 1

Post-Management Follow-up

• If surgery is performed, follow-up should include thyroid function testing and monitoring for recurrence based on the final pathology 1
• If the lesion proves to be malignant, TSH suppression therapy may be indicated depending on risk stratification 1
• Regular ultrasound surveillance of the remaining thyroid tissue and cervical lymph nodes should be performed at appropriate intervals 1

Conclusion

Based on the nodule's size, cytology findings, and NRAS mutation status, a wait-and-see approach is not recommended for this patient. Surgical management (at minimum a lobectomy) would provide definitive diagnosis and appropriate treatment for what is likely a neoplastic process with intermediate-to-high risk of malignancy.