Levothyroxine Monotherapy: What Works Better for the Individual With Hypothyroidism?

OBJECTIVE: I explore objective data not supporting the addition of liothyronine (medication) (LT3) to levothyroxine (medication) (LT4) in patients with hypothyroidism. Accurate identification of patients with symptomatic (almost exclusively overt) hypothyroidism is important in evaluating clinical outcomes of therapies. Recent studies have documented that nearly a third of individuals who are offered thyroid hormone are euthyroid at the time of initiation. Additionally, others are clinically diagnosed without biochemical confirmation, so a sizable proportion of those started on LT4 are not hypothyroid. The assumption that nonhypothyroid symptoms will resolve with LT4 is problematic. The true underlying cause of these symptoms remains unidentified and untreated. METHODS: In a narrative fashion I will review the positive predictive value of and correlation of symptoms consistent with hypothyroidism and confirmed hypothyroidism likely to favorably respond to thyroid hormone replacement. RESULTS: Following a review of the reliability of thyroid-stimulating hormone (TSH) in predicting a euthyroid state, the correlation of circulating triiodothyronine (serum measurement) (T3) levels with symptoms and predictive value of T3 to forecast the outcome of adding LT3 to LT4 will be reviewed. The utility of striving for high, middle, or low TSH set points within the expected range to predict changes in clinical quality of life and the ability of blinded patients to sense subtle differences along this spectrum will be documented. In addition, the clinical impact of single nucleotide polymorphisms in the type 2 deiodinase gene will be reviewed. Finally, the overall satisfaction of selected patients with their thyroid hormone treatments will be outlined and preferences for T3-containing treatments from blinded studies will be summarized. CONCLUSION: Basing thyroid hormone treatment decisions on patient symptoms likely results in missed diagnoses We should encourage primary care physicians to assess a differential diagnosis, exclude other diagnoses, and not assume a thyroid etiology when TSH is normal. Modifying treatment to a particular TSH target or adjusting based on a low T3 level does not seem to enhance patient outcomes. Finally, pending further trials of "symptomatic" participants, using sustained release LT3 to mimic normal physiology, and including monocarboxylate 10 transporter and Type 2 deiodinase polymorphisms and objective outcomes, I will continue to depend on therapy with LT4 monotherapy and seek alternative explanations for my patients' nonspecific symptoms.

Comparative Effectiveness of Persistent Use of a Name-Brand Levothyroxine (Synthroid®) vs. Persistent Use of Generic Levothyroxine on TSH Goal Achievement: A Retrospective Study Among Patients with Hypothyroidism in a Managed Care Setting.

INTRODUCTION: Levothyroxine monotherapy (Synthroid® or multiple generic levothyroxine [GL] formulations) is standard treatment for hypothyroidism. Our objective was to compare effectiveness (as measured by achievement of thyroid-stimulating hormone [TSH] levels) and economic outcomes of Synthroid vs. any one of multiple GLs in patients with hypothyroidism. METHODS: Data for this retrospective cohort study were obtained from the HealthCore Integrated Research Database®. All study patients had ≥ 2 claims between 1 January 2006 and 31 December 2017 with ICD-9/10-CM diagnosis codes for hypothyroidism; were persistent users of Synthroid vs. any GL; and had ≥ 1 TSH laboratory result during 12-month follow-up. Patients were divided into one of two cohorts based on index medication and were 1:1 matched using propensity scores. The primary outcome was the proportion of patients with last TSH laboratory result during follow-up within the reference range (0.3-4.12 mIU/L). Secondary outcomes included all-cause and hypothyroidism-related healthcare resource utilization (HCRU) and costs. RESULTS: After propensity score matching, the Synthroid and GL cohorts each contained 18,382 patients. At follow-up, significantly more patients receiving Synthroid were in the TSH reference range vs. GL (78.5% vs. 77.2%, respectively, p = 0.002). HCRU and costs were broadly similar between the cohorts in terms of all-cause inpatient hospitalizations, emergency department visits, outpatient services, and pharmacy fills. Irrespective of index medication, patients with TSH within the reference range had significantly lower hypothyroidism-related medical and total costs compared to those outside the range. CONCLUSIONS: This real-world data study showed Synthroid was associated with better TSH target achievement vs. GL in a US managed care population. Achieving TSH goals may provide substantial economic value by reducing hypothyroidism-related HCRU and costs.

Thyroid testing paradigm switch from thyrotropin to thyroid hormones-Future directions and opportunities in clinical medicine and research.

PURPOSE: Recently published papers have demonstrated that particularly in untreated individuals, clinical parameters more often associate with thyroid hormone, particularly free thyroxine (FT4), levels than with thyrotropin (TSH) levels. Clinical and research assessments of the thyroid state of peripheral tissues would therefore be more precise if they were based on FT4 levels rather than on TSH levels. In this paper we describe implications of, and opportunities provided by, this discovery. CONCLUSIONS: The FT4 level may be the best single test of thyroid function. The addition of free triiodothyronine (FT3) and TSH levels would further enhance test sensitivity and distinguish primary from secondary thyroid dysfunction respectively. There are opportunities to reconsider testing algorithms. Additional potential thyroidology research subjects include the peripheral differences between circulating FT4 and FT3 action, and outcomes in patients on thyroid replacement therapy in terms of thyroid hormone levels. Previously performed negative studies of therapy for subclinical thyroid dysfunction could be repeated using thyroid hormone levels rather than TSH levels for subject selection and the monitoring of treatment. Studies of outcomes in older individuals with treatment of high normal FT4 levels, and pregnant women with borderline high or low FT4 levels would appear to be the most likely to show positive results. There are fresh indications to critically re-analyse the physiological rationale for the current preference for TSH levels in the assessment of the thyroid state of the peripheral tissues. There may be opportunities to apply these research principles to analogous parameters in other endocrine systems.

Combined molecular and histologic end points inform cancer risk estimates for thyroid nodules classified as atypia of undetermined significance.

BACKGROUND: Thyroid nodules classified as atypia of uncertain significance (AUS) on fine-needle aspiration cytology are heterogeneous. Prior studies reported a higher risk of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)/cancer among AUS nodules that had cytologic (AUS-C) versus architectural (AUS-A) atypia; however, such studies were generally confined to resected cohorts, introducing bias into risk calculations. The authors hypothesized that combined histologic and molecular end points would permit clinically meaningful calculations of NIFTP/malignancy risk among AUS nodules. METHODS: The study consisted of 279 thyroid nodules classified as AUS on initial fine-needle aspiration and tested by the Afirma Gene Expression Classifier (GEC) between June 2013 and October 2017. Results of GEC testing and histopathologic diagnoses were stratified by AUS classifiers. The AUS-A category was further subclassified as 1) hypocellular microfollicular or 2) cellular with mixed but predominantly microfollicular architecture. NIFTP/cancer risk was calculated for each subgroup, with the inclusion of unresected nodules that had benign GEC results as low-risk end points comparable to histologically benign nodules. RESULTS: When only histologic end points were considered, there was no difference in NIFTP/cancer risk (25% vs 23%; P = .82). By using molecular and histologic end points, AUS cases with cytologic atypia trended toward higher NIFTP/cancer risk than AUS-A cases (14% vs 6%; P = .06). Furthermore, AUS-A cases showed a trend toward lower NIFTP/cancer risk for hypocellular microfollicular aspirates (3%) compared with cellular samples that had mixed/predominantly microfollicular architecture (13%; P = .18). CONCLUSIONS: The inclusion of unresected benign GEC nodules in risk-of-malignancy calculations provides more accurate results, which may be helpful for informing patient management as well as quality improvement in the cytopathology laboratory.

Repeat Fine Needle Aspiration Cytology Refines the Selection of Thyroid Nodules for Afirma Gene Expression Classifier Testing.

Background: Molecular testing (MT) refines risk stratification for thyroid nodules that are indeterminate for cancer by fine needle aspiration (FNA) cytology. Criteria for selecting nodules for MT vary and remain largely untested, raising questions about the best strategy for maximizing the usefulness of MT while minimizing the harms of overtesting. We used a unique data set to examine the effects of repeat FNA cytology-based criteria for MT on management decisions and nodule outcomes. Methods: This was a study of adults (age 25-90 years; 281 women and 72 men) with cytologically indeterminate (Bethesda III/IV) thyroid nodules who underwent repeat FNA biopsy and Afirma Gene Expression Classifier (GEC) testing (N = 363 nodules from 353 patients) between June 2013 and October 2017 at a single institution, with follow-up data collected until December 2019. Subgroup analysis was performed based on classification of repeat FNA cytology. Outcomes of GEC testing, clinical/sonographic surveillance of unresected nodules, and histopathologic diagnoses of thyroidectomies were compared between three testing approaches: (i) Reflex (MT sent on the basis of the initial Bethesda III/IV FNA), (ii) SemiRestrictive (MT sent if repeat FNA is Bethesda I-IV), and (iii) Restrictive (MT sent only if repeat FNA is Bethesda III/IV) testing approaches. Results: Restricting MT to nodules that remain Bethesda III/IV on repeat FNA would have missed 4 low-risk cancers and 3 noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) (collectively 2% of the test population) but would have avoided diagnostic surgery for 42 benign nodules (12% of the test population). The Restrictive testing strategy was more specific (delta 0.126 confidence interval [CI 0.093 to 0.159] and 0.129 [CI 0.097 to 0.161], respectively) but less sensitive (delta -0.339 [CI -0.424 to -0.253] and -0.340 [CI -0.425 to -0.255], respectively) than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer. Conclusions: Repeat FNA cytology can guide the selection of cytologically indeterminate thyroid nodules that warrant MT. The Restrictive model of performing Afirma GEC only on nodules with two separate biopsies showing Bethesda III/IV cytology would reduce the rate of diagnostic surgery for histologically benign nodules while missing only rare low-risk tumors. Given the low but nontrivial risks of thyroidectomy, the higher specificity of the Restrictive testing approach disproportionately outweighs the potential harms.

USE OF THE FREE THYROXINE INDEX TO REFINE THE LOWER LIMIT OF A FREE THYROXINE IMMUNOASSAY FOR DETECTION OF SECONDARY HYPOTHYROIDISM.

OBJECTIVE: To determine the utility of measuring free T4 index (FT4I) in patients with low free T4 (FT4) levels using immunoassay and normal thyroid-stimulating hormone for the evaluation of secondary hypothyroidism. METHODS: We performed a retrospective medical chart review of patients seen at a single institution as outpatients who had a simultaneously normal thyroid-stimulating hormone level, low FT4 level, and any FT4I measured between June 2014 and October 2016. Demographic, laboratory, and imaging data were collected. Using FT4I as the reference for diagnosis of hypothyroidism, the sensitivity and specificity of the FT4 immunoassay's lower-limit thresholds were determined. Within each threshold group, available brain imaging and biochemical evaluation were categorized according to the presence or absence of pituitary disease. RESULTS: A total of 155 sets of result pairs (FT4 and FT4I) performed on 118 subjects were analyzed. The lower limit of a normal FT4 level by immunoassay at this institution was 0.93 ng/dL, though all pairs with FT4 ≥0.89 ng/dL had a normal FT4I. All pairs with FT4 ≤0.67 ng/dL had a low FT4I. No pituitary macroadenomas were identified in any subject, though the rates of pituitary imaging in this patient sample were low. CONCLUSION: Patients with a borderline low FT4 level by immunoassay often have normal FT4I. In such patients at our center, significant structural and biochemical pituitary pathology was uncommon.

Effect of Levothyroxine on Kidney Function in Chronic Kidney Disease with Subclinical Hypothyroidism in US Veterans: A Retrospective Observational Cohort Study.

INTRODUCTION: Chronic kidney disease (CKD) may be associated with overt or subclinical hypothyroidism [SCH; defined as elevated serum thyroid-stimulating hormone (TSH) despite normal free thyroxine levels). Although some studies have demonstrated that thyroid replacement therapy may improve renal function in overt hypothyroidism, there is no consensus on its benefits in SCH. Clinical and limited economic outcomes were evaluated in levothyroxine-treated US veterans with CKD + SCH. METHODS: Veterans Health Administration claims data from April 2013 to March 2018 for levothyroxine-treated versus nontreated CKD + SCH patients were compared. Eligible patients with CKD + SCH (≥ 2 elevated TSH values recorded; ≥ 2 normal thyroxine values recorded) had ≥ 1 TSH values recorded during 24-month follow-up, and ≥ 1 estimated glomerular filtration rate (eGFR) measurement during baseline and follow-up. Continuous levothyroxine use (treatment cohort) was required during follow-up. The primary endpoint was eGFR at 6, 12, 18, and 24 months; secondary endpoints included eGFR change from baseline, CKD progression, and length of hospital stay (LOS). Propensity score matching (PSM) was performed. RESULTS: Of 453 eligible patients, 157 remained in each cohort after PSM. Most were male (96%) and white (88%); mean age was 75 years. No significant differences were observed between cohorts at any time point for eGFR, eGFR change from baseline, or CKD progression. Treated patients had numerically higher mean eGFR at 6 and 12 months, lower proportions of progression to higher CKD stages at 12, 18, and 24 months, and shorter mean all-cause LOS versus nontreated patients (1.92 vs. 3.30 days; P = 0.3483) within the 24-month follow-up period. A significantly shorter mean CKD-related LOS was observed versus nontreated patients (0.11 vs. 1.38 days; P < 0.0001) during the 24-month follow-up. CONCLUSION: Levothyroxine use was associated with economic and clinical benefit in some patients with CKD + SCH, despite an absence of overall benefit on eGFR; confirmatory research is needed.

The Association Between Switching from Synthroid® and Clinical Outcomes: US Evidence from a Retrospective Database Analysis.

INTRODUCTION: Clinical guidelines recommend levothyroxine as the standard of care for hypothyroidism and that patients should be treated with a consistent preparation of synthetic levothyroxine without switching among formulations. This study examines the likelihoods of negative clinical outcomes between continuous users of Synthroid® (AbbVie, Inc.) and patients who switch from Synthroid® to an alternative formulation of levothyroxine. METHODS: This retrospective cohort analysis utilized data from Optum Clinformatics™ DataMart covering May 1, 2000 to March 30, 2016. After 6 months of consistent use of Synthroid®, patients were categorized as continuous users or as switchers (by filling a prescription for an alternative formulation). Key outcomes included the likelihood of a thyroid-stimulating hormone (TSH) laboratory value out of a guideline recommended range and/or an adverse clinical composite endpoint identified by ICD codes in the patient's claims data over the following 2 years for any of the following: chronic kidney disease, depression, fatigue, heart failure, hyperlipidemia, hypertension, or obesity. Individual components of the composite endpoint were also examined. Outcomes were analyzed using multivariable logistic models on propensity score matched cohorts. Analyses controlled for patient characteristics using SAS 9.4 software. Chi-square and t tests were employed and P < 0.05 was pre-specified as statistically significant. RESULTS: Propensity score matching resulted in a sample of 9925 continuous users and 9925 switchers. Switchers were significantly more likely than continuers to have a TSH laboratory value out-of-range in the post-period [odds ratio (OR) 1.15; 95% confidence interval (CI) (1.08-1.23)]. Switchers were also more likely to have the composite clinical endpoint [OR 1.23; CI (1.12-1.37)] and to have individual diagnoses of chronic kidney disease, depression, fatigue, hypertension, or obesity in the post-period. CONCLUSIONS: Results of this large retrospective study over an extended time horizon support clinical guideline recommendations that switching among alternative formulations of synthetic levothyroxine should generally be avoided. Continuous use of Synthroid® was associated with a significantly higher likelihood of maintaining the TSH laboratory value within a guideline recommended range and a significantly lower likelihood of being diagnosed with adverse clinical outcomes.

Alternative routes of levothyroxine administration for hypothyroidism.

PURPOSE OF REVIEW: The aim of the article is to present the basics of oral levothyroxine (LT4) absorption, reasons why patients may have persistently elevated serum thyroid stimulation hormone (TSH) levels, and alternative strategies for LT4 dosing. RECENT FINDINGS: Although oral LT4 tablets are most commonly used for thyroid hormone replacement in patients with hypothyroidism, case studies report that liquid oral LT4, intravenous, intramuscular, and rectal administration of LT4 can successfully treat refractory hypothyroidism. SUMMARY: Hypothyroidism is one of the most common endocrine disorders encountered by primary care physicians and endocrinologists. LT4 is one of the most widely prescribed medications in the world and it is the standard of care treatment for hypothyroidism. Generally, hypothyroid patients will be treated with LT4 tablets to be taken orally, and monitoring will occur with routine serum thyroid tests, including TSH concentrations. However, many patients fail to maintain serum TSH levels in the target range while managed on oral LT4 tablets. A subset of these patients would be considered to have poorly controlled hypothyroidism, sometimes termed refractory hypothyroidism. For these patients, optimization of ingestion routines and alternative formulations and routes of administration of LT4 can be considered, including oral liquid, intravenous, intramuscular, and even rectal formulations.

Thyrotoxicosis after massive triiodothyronine (LT3) overdose: a coast-to-coast case series and review.

Excessive exogenous thyroid hormone ingestion may lead to severe thyrotoxicosis and cause potential harm. We have reviewed the literature and suggested that thyroid hormone supplementation should not be used to alleviate nonspecific complaints in patients with normal endogenous thyroid function. Failure to do so may cause serious harm, as demonstrated in one of the cases described here. In addition, treatment based on symptom relief only without biochemical measure may lead to overmedication - as reported from academic hospitals both in Canada and the United States. Given the risk of severe thyrotoxicosis from potential compounding errors, pharmacies providing a compounding service should be subject to more rigorous monitoring by the food and drug administration. Clinicians should also use local biochemical markers when titrating thyroid hormone supplements even though the normal thyroid function reference range has its limitation, failure to do so may result in iatrogenic thyrotoxicosis.

Nondiagnostic Fine-Needle Aspiration Biopsy of Thyroid Nodules: Outcomes and Determinants.

Background: Nondiagnostic results are common following fine-needle aspiration biopsy (FNAB) of thyroid nodules, but recommendations for the management of these patients vary. We sought to determine the outcomes and predictors of nondiagnostic FNABs in a single-center cohort of patients undergoing thyroid nodule evaluation. Methodology: We identified all first time ultrasound-guided FNABs performed between May 2007 and June 2013 at the Beth Israel Deaconess Medical Center Thyroid Nodule Clinic and examined demographic data, follow-up ultrasounds, repeated FNABs, and histopathologic findings. We examined the likelihood of diagnostic findings and of cancer with increasing numbers of nondiagnostic evaluations with their exact binomial confidence intervals [CIs] and potential predictors of nondiagnostic status using generalized estimating equations. Results: During the six-year period, 2234 unique individuals underwent ultrasound-guided FNAB of a thyroid nodule. The probability of obtaining a diagnostic biopsy declined from 84.4% [95% CI 82.8-85.8%] for initial FNABs to 57.6% [CI 50.8-64.2%] for the first re-FNAB and further to 42.4% [CI 25.5-60.8%] for second re-FNABs. Adjusted risk of nondiagnostic FNAB strongly increased with increasing numbers of previous biopsies and was also higher among whites. The overall rate of diagnosis of malignancy after a nondiagnostic FNAB was 8.1% [CI 4.2-13.7%] and was similar regardless of the number of previous nondiagnostic aspirations. Conclusion: Following an initial nondiagnostic FNAB, the probability of yielding a diagnostic result declines with each sequential repeat FNAB. Nonetheless, a tangible possibility of malignancy remains even after repeated nondiagnostic FNABs.

Systematic Review and Meta-analysis of the Impact of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) on Cytological Diagnosis and Thyroid Cancer Prevalence.

A re-named diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) likely impacts the prevalence of thyroid cancer and risk of malignancy in populations based on the established Bethesda System of Reporting Thyroid Cytopathology (TBSRTC). This study was done to investigate the prevalence and cytological distribution of NIFTP. PRISMA guided systematic review was done from a database search of Pubmed, EMBASE, and Medline using the search terms "non-invasive follicular thyroid neoplasm with papillary-like nuclear features", "non-invasive follicular variant of papillary carcinoma", "niftp", and "Bethesda" until November 2018. Original articles with surgically proven diagnoses of NIFTP using strict NIFTP criteria were included. Twenty-nine studies with 1563 cases of NIFTP were included. The pooled prevalence of NIFTP in cases which would be classified previously as the follicular variant of papillary thyroid cancer (FVPTC) and papillary thyroid cancer (PTC) were 43.5% (95% CI 33.5-54.0%) and 4.4% (95% CI 2.0-9.0%) respectively. The pooled TBSRTC distribution of cases diagnosed as NIFTP was: from the non-diagnostic category 3.6% (95% CI 2.4-5.3%), benign 10.0% (95% CI 7.2-13.6%), AUS/FLUS 34.2% (95% CI 28.2-40.8%), FN/SFN 22.7% (95% CI 17.2-29.4%), suspicious for malignancy 22.4% (95% CI 17.7-27.9%), and malignant 7.5% (95% CI 4.2-12.9%). While a significant reduction in FVPTC prevalence is anticipated, a modest reduction of PTC prevalence is also expected with adoption of the NIFTP terminology that would be distributed mainly among lesions classified as indeterminate thyroid nodules. Further studies are needed to identify unique clinical characteristics of these lesions preoperatively.

Thyroxine and treatment of hypothyroidism: seven decades of experience.

Hypothyroidism is one of the most common endocrine disorders, affecting as much as 10% of the global population. There is a rich cultural milieu of treatment history and interventions dating as far back as 2 millennia. Chinese cretins were treated with sheep thyroid in the 6th century. In 1890, transplanted animal thyroid tissue resulted in a prompt clinical response in a myxedematous patient, and in 1891 injections of sheep thyroid were reported. One year later, the oral administration of fresh sheep thyroid glands was noted to be effective. Within a few years, the danger of over-dosage with extracts was recognized and dosing guidance indicated a low dose start and gradual increase as required based on symptoms. Orally ingested extracts became widespread and by 1914 thyroxine had been crystallized. In 1927, thyroxine, was synthesized as an acid, limiting oral absorption. Finally a sodium salt of thyroxine was introduced in 1949. These synthetic preparations were then made available for clinical use. Prior to 1970, extracts and combination therapy with synthetic LT4 and LT3 were standard replacement until the peripheral deiodinase-mediated T4 to T3 conversion documented the endogenous generation of T3 from LT4 in athyreotic subjects. This resulted in advocacy for patients previously treated with combinations and desiccated thyroid be transitioned to L-thyroxine monotherapy. The determination of the optimal dose has evolved such that now a general recommendation for replacement dosage of LT4 is 1.6-1.7 mcg/kg/day. Thyroid hormone extracts were established prior to the FDA's establishment in 1906, and when the Food, Drug, and Cosmetic act of 1938 enhanced the FDA's regulatory authority. In 1997, FDA declared LT4 products to be new drugs subject to regulation and quickly a pharmacokinetic process to determine interchangeability among approved LT4 products ensued. Differences in bioavailability of 12.5% or more may be considered therapeutically equivalent and therefore such products interchangeable. To assure refill to refill consistency, all levothyroxine sodium products now meet a 95-105% potency specification throughout their labeled shelf-lives. Seventy years after Kendall's great achievement in isolating thyroxine, we have thyroxine products with precise amounts of synthetic hormone that meet demanding regulations to assure high product quality, predictable bioavailability given its narrow therapeutic range, and now are left with potential variance in the therapeutic efficacy among different preparations.

Cytomorphology of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and the Impact of New Nomenclature on Molecular Testing.

The re-naming of noninvasive follicular variant papillary thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of malignancy rates, thereby affecting mutation frequency in papillary thyroid cancer. Preoperative assessment of such nodules could affect management in the future. The original publications following the designation of the new nomenclature have been extensively reviewed. With the adoption of NIFTP terminology, a reduction in the follicular variant of papillary thyroid cancer (FVPTC) prevalence is anticipated, as is a modest reduction of papillary thyroid cancer (PTC) prevalence that would be distributed mainly across indeterminate thyroid nodules. Identifying NIFTP preoperatively remains challenging. RAS mutations are predominant but the presence of BRAF V600E mutation has been observed and could indicate inclusion of the classical PTC. The histological diagnosis of NIFTP to designate low-risk encapsulated follicular variant papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby altering the mutation prevalence. The histopathologic criteria have recently been refined with an exclusion of well-formed papillae. The preoperative identification of NIFTP using cytomorphology and gene testing remains challenging.