State-of-the-art Thyroid Surgical Recommendations in the Era of Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features : AHNS Endocrine Surgery Guidelines

RL Ferris, Y Nikiforov, DJ Terris, RR Seethala, JA Ridge,
P Angelos, QY Duh, R Wong, MM Sabra, JA Fagin, B McIver, VJ Bernet, RM Harrell, N Busaidy, ES Cibas, WC Faquin,
P Sadow, Z Baloch, M Shindo, L Orloff, L Davies, G Randolph

1. State-of-the-art T hyroid S urgical R ecommendations in the Era of Noninvasive F ollicular T hyroid N eoplasm with Papillary -like Nuclear F eatures RL Ferris, Y Nikiforov , DJ Terris, RR Seethala , JA Ridge, P Angelos, QY Duh, R Wong, MM Sabra, JA Fagin, B McIver, VJ Bernet, RM Harrell, N Busaidy , ES Cibas , WC Faquin , P Sadow , Z Baloch , M Shindo , L Orloff , L Davies, G Randolph

2. T o synthesize a collaborative, state-of-the-art guideline regarding noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and its implications for surgical planning To promote best uniform practices and encourage safe and successful outcomes Purpose

3. A noninvasive tumor of thyroid follicular cells with a follicular growth pattern and nuclear features of papillary thyroid carcinoma Extremely low malignant potential Considered premalignant rather than benign NIFTP cannot be definitively diagnosed preoperatively NIFTP is a surgical target Diagnosis can only be made after exclusion of invasion N oninvasive Follicular Thyroid Neoplasm with Papillary -like Nuclear Features (NIFTP)

4. Paradigm shift affects clinical management Suspected presence of NIFTP leads to more conservative management Cannot be definitively diagnosed preoperatively Predicting its presence relies on preoperative speculation NIFTP Presurgical Evaluation

5. NIFTP is considered a precancer Requires surgical removal and histologic evaluation Existence of NIFTP results in a decreased rate of thyroid cancer overall Lobectomy versus total thyroidectomy in appropriately selected patients Total thyroidectomy still remains a valid and acceptable option N oninvasive Follicular Thyroid Neoplasm with Papillary -like Nuclear Features (NIFTP)

6. Historically , histologic outcome of FNA included hyperplastic/ adenomatoid nodule, follicular adenoma, follicular carcinoma, and follicular variant of papillary thyroid carcinoma (FVPTC) Reclassification of noninvasive FVPTC as NIFTP has implications for practice of cytopathology. Decrease in the implied risk of malignancy NIFTP should be in the differential diagnosis Cytologic features can be used to exclude a diagnosis of NIFTP in favor of a classical PTC diagnosis Cytology, Fine Needle Aspiration & NIFTP

7. Cytopathology Features Supportive of NIFTP Diagnosis

8. Preoperative Features May Indicate NIFTP

9. Primarily associated with activating mutations of 1 of the 3 RAS genes (NRAS>HRAS>>KRAS ) Majority lead to codon 61 glutamine substitutions Other driver mutations in NIFTP include: PAX8-PARG, THADA fusions, and BRAF K601E mutations Key aspect of NIFTP is absence of BRAF V600E ,TERT, RET, and NTRK fusions and other mutations associated with classical and tall cell variant PTCS These mutations should not be encountered in appropriately diagnosed NIFTPs No mutations present in NIFTPs are pathognomonic Molecular Testing and NIFTP

10. Ultrasound findings coupled with cytomorphologic features can be used to triage intermediate NFA categories in regard to NIFTP preoperative detection Ultrasound for an invasive FVPTC typically reveals at least one of these features: Markedly hypoechoic Taller-than-wide Microcalcifications Blurred margins with an avascular Doppler pattern Ultrasound and NIFTP

11. Ultrasound and NIFTP

12. Surgical Considerations T otal thyroidectomy indicated if: Significant contralateral lobe nodules Lymph node metastases Tumor fixation Vocal cord paralysis or voice changes Posterior capsule tumor abutment on imaging Clear radiographic evidence for extrathyroidal extension

13. Surgical Considerations Patient’s willingness to have completion surgery if needed Patient’s medical fitness for second surgery if needed Multidisciplinary team as a whole should be comfortable with plans for less extensive surgery

14. NIFTP are a new thyroid tumor diagnostic category and prospective follow-up of patients with these tumors does not exist Diagnosis of NIFTP should not be based on retrospective interpretation of written pathologic reports created before May of 2016 Care for each patient with thyroid nodular disease should ultimately be determined by evidence - based, individualized clinical judgment N oninvasive Follicular Thyroid Neoplasm with Papillary -like Nuclear Features (NIFTP)

15. Patients with resected solitary NIFTP require less active follow-up Measurement of yearly quantitative thyroglobulin in patients with NIFTP is appropriate Sufficient to maintain normal range TSH If thyroid tissue remains in the neck, a neck ultrasound should be considered every 1-2 years for the first decade NIFTP frequently present with concurrent microcarcinomas and macrocarcinomas If a tumor is associated with a NIFTP lesion, follow-up should be based on the coexisting malignant lesion N oninvasive Follicular Thyroid Neoplasm with Papillary -like Nuclear Features (NIFTP)

16. Pathologic diagnosis is made based on follicular growth pattern, encapsulation and its hallmark nuclear cytology The diagnosis of NIFTP should not be made retrospectively due to the requirement to sample the entire tumor and tumor/parenchymal interface Retrospective Diagnosis of NIFTP

17. Low recurrence risk for NIFTP Additional studies needed NIFTP diagnostic errors may occur in both follicular and papillary lineage directions. There is a need for thorough histopathologic examination and following stringent criteria to diagnose NIFTP Better understanding is needed to define whether or not NIFTP lesions of large size have a similarly low risk of recurrence. Conclusion

18. State-of-the-art T hyroid S urgical R ecommendations in the Era of Noninvasive F ollicular T hyroid N eoplasm with Papillary -like Nuclear F eatures RL Ferris, Y Nikiforov , DJ Terris, RR Seethala , JA Ridge, P Angelos, QY Duh, R Wong, MM Sabra, JA Fagin, B McIver, VJ Bernet, RM Harrell, N Busaidy , ES Cibas , WC Faquin , P Sadow , Z Baloch , M Shindo , L Orloff , L Davies, G Randolph