Papillary-like Nuclear Features Research Articles

Impact of ultrasound elastography in evaluating Bethesda category IV thyroid nodules with histopathological correlation

IntroductionFine needle aspiration (FNA) is the gold standard method recommended in the diagnosis of thyroid nodules. Bethesda IV cytology results are identified in 7-9% of nodules investigated through FNA, with reported malignancy rate in a wide range of 10-40%. The recommended treatment is either surgical or risk additional molecular testing before surgery. However, a large number of nodules belonging to this category (60-80%) are observed to be benign after surgical excision, which can put the patient at risk of unnecessary surgical morbidity. This study aimed to assess the diagnostic performance of conventional ultrasound, the ACR TI-RADS score and elastography in cases of Bethesda IV cytology on FNA.MethodsWe evaluated ninety-seven consecutive cases with Bethesda category IV results on FNA by using conventional B-mode ultrasound, qualitative strain or shear-wave elastography (Hitachi Preirus Machine, Hitachi Inc., Japan and Aixplorer Mach 30 Supersonic Imagine, Aix-en-Provence, France) and all nodules were classified according to the ACR TI-RADS system. Conventional ultrasound was used to categorize the nodules as potentially malignant based on the following features: hypoechogenicity, inhomogeneity, a taller than wide shape, irregular margins, presence of microcalcifications, an interrupted thyroid capsule and suspicious cervical lymph nodes. Elastography classified nodules with increased stiffness as suspicious for malignancy.ResultsWe considered pathology results as the gold standard diagnosis, finding that 32 out of 97 nodules were carcinomas (33%) and 65 out of 97 were benign nodules (67%). The benign group included twenty cases of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Finally, we compared ultrasound data with pathology results, which showed that nineteen out of the 32 malignant nodules presented with increased stiffness on elastography (p=0.0002). On conventional ultrasound, we found that microcalcifications (p=0.007), hypoechogenicity and irregular margins (p=0.006) are features which can distinguish between benign and malignant nodules with statistical significance.DiscussionIntegrating elastography as a parameter of the ACR TI-RADS score in the evaluation of Bethesda category IV nodules showed a sensitivity of 90.62% in detecting thyroid cancer cases (p=0.006). We can conclude that elastographic stiffness as an addition to high risk features observed on conventional ultrasound improves the detection of malignant nodules in cases with Bethesda IV cytology.

Diagnostic-therapeutic management in patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

Diagnostic-therapeutic management in patients with non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

Discriminating Interpatient Variabilities of RAS Gene Variants for Precision Detection of Thyroid Cancer.

Interpatient variabilities in genomic variants may reflect differences in tumor statuses among individuals. To delineate interpatient variabilities in RAS variants in thyroid tumors based on the fifth World Health Organization classification of thyroid neoplasms and assess their diagnostic significance in cancer detection among patients with thyroid nodules. This prospective diagnostic study analyzed surgically resected thyroid tumors obtained from February 2016 to April 2022 and residual thyroid fine-needle aspiration (FNA) biopsies obtained from January 2020 to March 2021, at Mount Sinai Hospital, Toronto, Ontario, Canada. Data were analyzed from June 20, 2022, to October 15, 2023. Quantitative detection of interpatient disparities of RAS variants (ie, NRAS, HRAS, and KRAS) was performed along with assessment of BRAF V600E and TERT promoter variants (C228T and C250T) by detecting their variant allele fractions (VAFs) using digital polymerase chain reaction assays. Interpatient differences in RAS, BRAF V600E, and TERT promoter variants were analyzed and compared with surgical histopathologic diagnoses. Malignancy rates, sensitivity, specificity, positive predictive values, and negative predictive values were calculated. A total of 438 surgically resected thyroid tumor tissues and 249 thyroid nodule FNA biopsies were obtained from 620 patients (470 [75.8%] female; mean [SD] age, 50.7 [15.9] years). Median (IQR) follow-up for patients who underwent FNA biopsy analysis and subsequent resection was 88 (50-156) days. Of 438 tumors, 89 (20.3%) were identified with the presence of RAS variants, including 51 (11.6%) with NRAS, 29 (6.6%) with HRAS, and 9 (2.1%) with KRAS. The interpatient differences in these variants were discriminated at VAF levels ranging from 0.15% to 51.53%. The mean (SD) VAF of RAS variants exhibited no significant differences among benign nodules (39.2% [11.2%]), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTPs) (25.4% [14.3%]), and malignant neoplasms (33.4% [13.8%]) (P = .28), although their distribution was found in 41.7% of NIFTPs and 50.7% of invasive encapsulated follicular variant papillary thyroid carcinomas (P < .001). RAS variants alone, regardless of a low or high VAF, were significantly associated with neoplasms at low risk of tumor recurrence (60.7% of RAS variants vs 26.9% of samples negative for RAS variants; P < .001). Compared with the sensitivity of 54.2% (95% CI, 48.8%-59.4%) and specificity of 100% (95% CI, 94.8%-100%) for BRAF V600E and TERT promoter variant assays, the inclusion of RAS variants into BRAF and TERT promoter variant assays improved sensitivity to 70.5% (95% CI, 65.4%-75.2%), albeit with a reduction in specificity to 88.8% (95% CI, 79.8%-94.1%) in distinguishing malignant neoplasms from benign and NIFTP tumors. Furthermore, interpatient differences in 5 gene variants (NRAS, HRAS, KRAS, BRAF, and TERT) were discriminated in 54 of 126 indeterminate FNAs (42.9%) and 18 of 76 nondiagnostic FNAs (23.7%), and all tumors with follow-up surgical pathology confirmed malignancy. This diagnostic study delineated interpatient differences in RAS variants present in thyroid tumors with a variety of histopathological diagnoses. Discrimination of interpatient variabilities in RAS in combination with BRAF V600E and TERT promoter variants could facilitate cytology examinations in preoperative precision malignancy diagnosis among patients with thyroid nodules.

NIFTP-adjusted risk estimation of Bethesda thyroid cytology categories should consider the indication for FNA according to TIRADS.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was firstly described in 2016. Since NIFTP is thought a non-malignant tumor, the Bethesda system for thyroid cytology proposes two estimations of risk of malignancy of the diagnostic categories, one considering NIFTP as cancer and another one considering it as a benign neoplasm. The present study aimed to review NIFTPs in a single center, re-assess them across categories of three Thyroid Imaging Reporting and Data Systems (TIRADSs), and define the indication for biopsy according to the category-specific size cut-offs. The study period was from 2017 to 2023. The institutional database was searched for histologically proven NIFTPs with preoperative ultrasound images. NIFTPs were re-assessed according to the American College of Radiology (ACR), European (EU), and Korean (K) TIRADSs. The indication for biopsy was defined according to TIRADS category-specific size threshold. Twenty NIFTPs from 19 patients were included. The median size of the NIFTPs was 23 mm. According to ultrasound, 80-85% of NIFTPs were at low-intermediate risk and 5-15% at high risk without significant difference among the tree TIRADSs (p = 0.91). The indication for FNA, according to three TIRADSs, was found in 52-58% of cases with no significant difference among systems (p = 0.96). NIFTPs have heterogeneous presentation according to TIRADSs with very low indication rate for FNA.

Ultrasound and cytopathological characteristics of thyroid tumours of uncertain malignant potential - from diagnosis to treatment.

The latest World Health Organization (WHO) classification from 2022 distinguishes the division of low-risk thyroid neoplasms such as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), follicular tumour of uncertain malignant potential (FT-UMP), and well-differentiated tumour of uncertain malignant potential (WDT-UMP). The final diagnosis is made postoperatively according to histopathologic results. The aim of the study was the assessment of ultrasonographic and cytopathological features of borderline lesions to predict low-risk tumours preoperatively and plan the optimal treatment for that group of patients. A total of 35 patients (30 women; 5 men), aged 20-81 years with a mean age of 49 years, were enrolled in the study. The study evaluated 35 focal lesions of the thyroid gland, classified as low-risk neoplasms according to the WHO 2022 classification: FT-UMP (n = 21), NIFTP (n = 7), and WDT-UMP (n = 7). Ultrasonographic features of nodules including contrast-enhanced ultrasound (CEUS) and elastography were assessed by 2 specialists, and the risk of malignancy was evaluated according to EU-TIRADS-PL classification. Of the 35 focal thyroid lesions, most were categorised as low or intermediate risk of malignancy according to EU-TIRADS-PL, with dominant category 3 [n = 13 (37.2%)] and category 4 [n = 15 (42.8%)]. High-risk category 5 was assessed in 7 lesions (20%). In cytopathology nodules were categorised as follows (Bethesda System TBSRTC 2023): Bethesda II (n = 4), Bethesda III (n = 2), Bethesda IV (n = 25), Bethesda V (n = 3), and Bethesda VI (n = 1). In the CEUS study, contrasting patterns dominated compared to the surrounding parenchyma, such as enhancement equal to the parenchyma (66.6%) or intense (28.5%), heterogeneous (61.9%), centripetal (42.8%), or diffuse (57.1%) with fast (33.3%) or compared to parenchyma contrast wash-in (42.8%) and its fast (33.3%) or comparable to thyroid parenchyma wash-out (52.3%). The study indicates that lesions with uncertain malignant potential typically present features suggesting low to intermediate risk of malignancy based on EU-TIRADS-PL classification, with dominant cytopathologic Bethesda IV category. However, 20% of lesions were assessed tas EU-TIRADS-PL category 5. Low-risk tumours, including NIFTP, FT-UMP, and WDT-UMP, require careful observation and monitoring post surgical treatment due to their potential for recurrence and metastasis. The preoperatively prediction of borderline tumour may play an important role in proper treatment and follow-up.

Abstract 2276: Comprehensive analysis of the genomic landscape of thyroid cancer

Abstract Thyroid cancer, the most common endocrine malignancy, has a high incidence worldwide. Meanwhile, the incidence of thyroid cancer ranks first in Korea. To assess the possible influence of ethnicity on the molecular profile of thyroid cancer, we compared the genomic features of South Korean thyroid cancer with European thyroid cancer. In this study, we performed whole genome sequencing profiling (WGS) for 459 Korean thyroid cancer patients, including papillary thyroid carcinoma (PTC, n = 274), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP, n =18), follicular thyroid carcinoma (FTC, n = 16), follicular thyroid adenoma (FTA, n = 63), Hürthle cell adenoma (HCA, n = 22), and invasive encapsulated follicular variant papillary thyroid carcinoma (IEFVPTC, n = 19). We assessed the single nucleotide variant (SNV) and insertions and deletions using Mutect2, Varscan2, and Strelka2. For mutation signature and copy number alterations analysis, we used the Maftools and GISTIC2.0 packages, respectively. Our results revealed that most somatic mutations were similar between the Korean thyroid cancer dataset and the cancer genome atlas program (TCGA). However, the Korean cohort (1%) had a much lower NRAS mutation frequency than the TCGA cohort (8%). Mutation signature analysis showed that SBS6 and SBS2 were highly associated with the TCGA and Korean cohort. SBS6 is related to defective DNA mismatch repair, and SBS2 is characterized predominantly by CC &amp;gt; TT doublet base substitutions. In addition, we identified the NIFTP-specific somatic mutations such as KEAP1 and ZFP36L2. This study presents insights into the genomic landscape of Korean thyroid cancer and reveals some similarities and differences with European thyroid cancer at the molecular level. Citation Format: SooHyun Im, Jong-Lyul Park, Jae-Yoon Kim, Chan-Kwon Jung, Seon-Young Kim. Comprehensive analysis of the genomic landscape of thyroid cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2276.

Nodal metastasis in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

Nodal metastasis in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

The Role of 5-Hydroxymethylcytosine as a Potential Epigenetic Biomarker in a Large Series of Thyroid Neoplasms.

Cytosine modifications at the 5-carbon position play a critical role in gene expression regulation and have been implicated in cancer development. 5-Hydroxymethylcytosine (5hmC), arising from 5-methylcytosine (5-mC) oxidation, has shown promise as a potential malignancy marker due to its depletion in various human cancers. However, its significance in thyroid tumors remains underexplored, primarily due to limited data. In our study, we evaluated 5hmC expression levels by immunohistochemistry in a cohort of 318 thyroid tumors. Our analysis revealed significant correlations between 5hmC staining extension scores and nodule size, vascular invasion, and oncocytic morphology. Nuclear 5hmC staining intensity demonstrated associations with focality, capsule status, extrathyroidal extension, vascular invasion, and oncocytic morphology. Follicular/oncocytic adenomas exhibited higher 5hmC expression than uncertain malignant potential (UMP) or noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), as well as malignant neoplasms, including papillary thyroid carcinomas (PTCs), oncocytic carcinomas (OCAs), follicular thyroid carcinomas (FTCs), and invasive encapsulated follicular variants of PTC (IEFV-PTC). TERT promoter mutation cases showed notably lower values for the 5hmC expression, while RAS (H, N, or K) mutations, particularly HRAS mutations, were associated with higher 5hmC expression. Additionally, we identified, for the first time, a significant link between 5hmC expression and oncocytic morphology. However, despite the merits of these discoveries, we acknowledge that 5hmC currently cannot segregate minimally invasive from widely invasive tumors, although 5hmC levels were lower in wi-FPTCs. Further research is needed to explore the potential clinical implications of 5hmC in thyroid tumors.

EphB3 protein is a potential ancillary diagnostic biomarker for thyroid cancers

ObjectiveTo investigate the expression of ephrin type B receptor 3 (EphB3) in thyroid tumors and its usage as an ancillary diagnostic biomarker for thyroid tumors. MethodsFormalin-fixed and paraffin-embedded (FFPE) tissue samples (78 cases) and FNAC samples (57 cases) were assessed with the EphB3 antibody using immunohistochemistry. PTC and other thyroid follicular tumors were compared regarding their EphB3 expression. Sanger sequencing was used to assess for the presence of a BRAF V600E mutation. ResultsEphB3 was positive in 81.8 % (27/33) of papillary thyroid carcinoma (PTC), 83.3 % (5/6) of medullary thyroid carcinoma (MTC), 25 % (1/4) of hyperplastic/adenomatoid nodule (HN), 14.3 % (1/7) of follicular adenoma (FA), and negative in follicular tumors of uncertain malignant potential (FT-UMP) (0/13), noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) (0/7), thyroid follicular carcinoma (TFC) (0/4), Hashimoto's thyroiditis (0/4), and normal thyroid follicular tissues (0/33). In cellular blocks, EphB3 was positive in 87.1 % (20/23) of PTC, 75 % (3/4) of MTC, 20 % (2/10) of HN, and negative in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (0/20) and normal thyroid follicular cells (0/10). ConclusionEphB3 is expressed in the majority of PTC, but less so in benign follicular nodules. EphB3 expression in fine needle aspiration cytology (FNAC) specimens can be used as a diagnostic tool to differentiate thyroid cancer from other follicular lesions in its differential diagnosis, especially AUS/FLUS and PTC.

Use of the Afirma Xpression Atlas for cytologically indeterminate, Afirma Genomic Sequencing Classifier suspicious thyroid nodules: Clinicopathologic analysis with postoperative molecular testing.

Afirma has recently introduced its Xpression Atlas (XA) as an adjunct to its Genomic Sequencing Classifier (GSC) for risk stratification of cytologically indeterminate thyroid nodules. We evaluated the performance of Afirma XA and associated pathologic findings for Afirma GSC suspicious nodules. Intradepartmental records of thyroid fine-needle aspirations (FNAs) from January 2021 to December 2022 were identified and reviewed for patient and nodule characteristics, FNA findings, molecular test results, and final surgical pathology, if available. Material for Afirma GSC testing was collected in 624 thyroid FNAs, and 148 (24%) were classified as cytologically indeterminate. Afirma GSC testing was successful in 132 (89%) of those cases, of which 35 (27%) were Afirma GSC suspicious. Afirma XA testing was positive in 11 cases (11/35 [31%]). Eight (73%) patients underwent surgery that revealed 7 patients with papillary thyroid carcinoma and 1 patient with noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) (risk of malignancy: 100% [8/8]). Among the 24 patients with negative Afirma XA results, 19 (79%) underwent surgery, revealing 5 patients with malignancy and 3 patients with NIFTP (risk of malignancy: 42% [8/19]). Overall, the risk of malignancy for Afirma GSC suspicious nodules was 59% (16/27). Afirma XA improved risk stratification of thyroid disease with a high risk of malignancy in Afirma GSC suspicious nodules. A negative Afirma XA result, however, should not be used as a rule-out test.

Prevalence and diagnostic significance of non-invasive follicular thyroid neoplasm with papillary-like nuclear features in Japan-A multi-institutional study.

This multi-institutional study investigated non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) frequency and its diagnostic significance in Japan. We reviewed 4008 thyroid nodules resected in six institutions before NIFTP was proposed. Overall, 26 cases diagnosed as non-invasive encapsulated follicular variant of papillary thyroid carcinoma (PTC) and 145 cases of follicular thyroid adenoma (FTA) were included. Of these nodules, 80.8% and 31.0%, respectively, were NIFTPs. In five institutions, NIFTPs were more commonly found in FTA than in PTC nodules. When NIFTP was included with PTC, the overall prevalence was 2.3%, with rates in five institutions below 5.0% (0.8%-4.4%). One NIFTP case with nuclear score 3 revealed nodal metastasis 2.5 years post-resection, and the carcinoma cells were immunohistochemically positive for BRAF. FTAs or NIFTPs with nuclear score 2 did not metastasize. NIFTP was more common among FTA than among PTC nodules, possibly due to underdiagnosis of PTC on nuclear findings. Considering the clinical findings, molecular pathogenesis, and therapeutic strategy in Japan, NIFTP with nuclear score 2 is not different from FTA, and use of this entity terminology is not meaningful. In contrast, NIFTP with nuclear score 3 has potential for metastasis and BRAFV600E mutation. Therefore, in NIFTP cases, nuclear scores 2 and 3 should be separately reported.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in Mureș County, Romania: Incidence and impact of reclassification over a six-year period (2016-2021)

Abstract Objective: In 2016 a group of expert endocrine pathologists proposed a new terminology, NIFTP (Non-invasive follicular thyroid neoplasm with papillary-like nuclear features) for a histological subtype of thyroid carcinoma (encapsulated follicular variant of papillary thyroid carcinoma, non-invasive type). In this study, we aimed to assess on a retrospective basis the epidemiological trend and overall incidence of NIFTP in Mureș county, Romania, over a six-year period (2016-2021). Methods: All NIFTPs registered between 2016-2021 in Târgu-Mureș Pathology Departments were reevaluated. NIFTP’s incidence was calculated by dividing the number of NIFTPs with the number of papillary thyroid carcinomas (PTCs). Further on, we compared NIFTP’s incidence between 2016-2018 with NIFTP’s incidence between 2019-2021, as the diagnostic criteria of NIFTP were revised in 2018. Results: Forty-six cases of NIFTP were registered in our departments between 2016-2021, resulting in an overall NIFTP incidence of 17.9 % [CI (95%): 7.6-32.5] among the 257 PTCs. When we compared the NIFTP’ incidence between the two study periods (2016-2018 versus 2019-2021), our data revealed that the NIFTP’s overall incidence has dropped from 21.4 % [CI (95%): −14.5-60.1] to 15% [CI (95%): −8.2-43] in the second evaluated period (p=0.034). Conclusion: The overall NIFTP incidence was low in our departments between 2016-2021. Moreover, NIFTP’s incidence decreased after 2018, following revision of the diagnostic criteria. Our results highlight that very stringent morphologic criteria need to be apply when making a diagnosis of NIFTP, in order to avoid a misdiagnosis and/or an overtreatment of a tumor with indolent behavior.

“Your cancer is no longer considered cancer”: Psychological reactions to reclassification information and communication preferences

In 2016, the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This reclassification removed the word “carcinoma” and the definition of cancer from the diagnosis. While the nomenclature change was expected to psychologically impact patients, that question has not been systematically explored. Using qualitative methods, we aimed to explore the psychological impact of reclassification on thyroid cancer patients and their preferences for receiving reclassification information. Semi-structured interviews with nine non-EFVPTC thyroid cancer survivors were conducted. Participants were presented with a hypothetical reclassification scenario, and interview transcripts were analyzed using a thematic content analytic approach. Participants expressed a range of psychological reactions to reclassification information, primarily negative, including anger, mistrust, and uncertainty, but also relief. All participants expressed difficulty understanding the concept of reclassification. Communication preferences favored conversation with an established medical provider over written materials, such as a letter. Communication must align with patient preferences. Being mindful of potential negative psychological reactions when providing information on cancer reclassification is vital. This study examines reactions to cancer reclassification information and preferences for how this information should be communicated.

NIFTPs may be reclassified not only from FVPTCs but also from follicular adenomas.

Few studies have focused on reclassifying follicular adenomas (FAs) as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), but none have been conducted in America or Europe. The aims of this study were to analyze the prevalence of NIFTP reclassified from follicular variant of papillary thyroid carcinomas (FVPTCs) and FAs before NIFTP was defined in the literature, the rate of NIFTP among PTC (papillary thyroid carcinomas) established in real time between 2017 and 2022, and demographic, ultrasonographic, and cytologic characteristics of NIFTPs compared with FVPTCs and FAs. This was a retrospective cohort study of tumors diagnosed as PTCs (n = 247) and FAs (n = 144) at a Brazilian hospital. Overall, 13.4% of PTCs and 7% of FAs were reclassified as NIFTPs. The rate of real-time diagnosed NIFTPs among PTC was 12.3%. The median tumor size was larger among NIFTPs (3.0 cm) than FVPTCs (1.1 cm; P < 0.01). A high-risk ultrasonographic pattern was rare in NIFTPs (5.6%). The cytologic classifications differed between FVPTCs and NIFTPs (P < 0.01), and the most frequent category among NIFTPs was 'follicular neoplasm' (52.6%). The category 'suspicious for malignancy' was frequent in FVPTCs and rare (5.3%) in NIFTPs. In conclusion, FVPTCs and FAs may be reclassified as NIFTPs. The prevalence of NIFTPs reclassified from FAs was lower in our cohort than in Asian studies. The rate of NIFTPs reclassified from PTC was similar to that of NIFTPs diagnosed in real time and was aligned with rates reported in studies from America and Europe. Preoperative features could not differentiate NIFTPs from FVPTCs or FAs.

A Comparative Study on BRAFV600E Mutation, Sonographic Findings, and Pathologic Characteristics in Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) and Invasive Follicular Variant of Papillary Thyroid Carcinoma (IFVPTC)

Objective: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) comprise a new subgroup of thyroid tumors of follicular origin with borderline histologic features that lack evidence of either capsular or vascular invasion. In contrast to the invasive follicular variant of papillary thyroid carcinoma (IFVPTC), adverse events such as cancer-related death, distant or regional metastases, and structural or biochemical recurrence do not occur in patients with NIFTP. Many studies have been done to elucidate these two specific types of papillary thyroid cancer (PTC) and reduce aggressive therapeutic actions. This study compares molecular, cytological, and radiologic features of NIFTP and IFVPTC. Methods &amp; Materials: Two groups of patients with NIFTP and IFVPTC (n = 18 in each group) who were referred to the endocrine clinic, at Imam Reza Hospital, were enrolled in this cross-sectional study. Molecular analysis for BRAFV600E mutation of thyroid tissue was evaluated for all cases. Patient data included: age, sex, type of surgery, thyroid sonographic findings, and prior cytological diagnosis with the Bethesda system for reporting thyroid cytopathology. Results: Only two cases in the IFVPTC group were positive for BRAFV600E mutation. The majority of NIFTP cases were diagnosed as benign lesions (8/18). In contrast, the majority of IFVPTC cases were diagnosed as suspicious for malignancy on cytology (7/18). The mean nodule size in ultrasound in the NIFTP group (41.81 ± 20.43 mm) was larger than the IFVPTC group (36.72 ± 20.73 mm) (p =0.47). Most cases in the IFVPTC group had significantly multiple nodules (72.2%), while most cases in the NIFTP group (81.3%) had solitary nodules. Nodule composition in both groups was solid and complex; however, no cystic nodules were detected in ultrasound examinations. Furthermore, no calcification or lymphadenopathy was seen in the majority of cases in ultrasound. In the IFVPTC group, 47.1% and 35.3% of nodules were hyperechoic and hypoechoic, respectively, while 23.1%, 38.5%, and 23.1% of nodules in the NIFTP group were heterogenic, hyperechoic, and hypoechoic, respectively. Conclusion: According to our findings, only 11.1% of IFVPTC cases were BRAFV600E-positive, while none of the patients in the NIFTP group showed this mutation. However, IFVPTC was predominantly associated with a preceding diagnosis of PTC on FNA, and NIFTP was associated with the preceding diagnosis of benign lesions and follicular neoplasm. Sonographic findings failed to distinguish NIFTP from IFVPTC.

A retrospective analysis of molecular testing in cytologically indeterminate thyroid nodules with histologic correlation: Experience at a heterogenous multihospital system.

Thyroid malignancy is one of the most common types of cancer in developed nations. Currently, fine-needle aspiration cytology (FNAC) is the most practical screening test for thyroid nodules. However, cytologically indeterminate samples comprise approximately 15%-30% of cases. These include cases classified as atypia of undetermined significance (AUS), follicular neoplasm (FN), and suspicious for malignancy (SFM). Indeterminate cases can be sent for molecular testing for more definitive classification to help guide management and prevent overtreatment of benign thyroid nodules. We conducted a retrospective review on molecular testing of indeterminate thyroid FNAC and reviewed subsequent histologic diagnoses in resection specimens to assess how molecular testing supported a diagnosis and its effect on clinical management of patients at our institution. A retrospective chart review was performed on all thyroid FNAC specimens, corresponding molecular testing, and subsequent surgical resection specimens over a 6-year period. A total of 10,253 thyroid FNAC were performed in our hospital system during our study period, of which 10% (n = 1102/10,253) had indeterminate FNAC results. Molecular testing was performed in 16% (n = 178/1102) of indeterminate cytology cases. Genetic alterations were identified in 39% (n = 69/178) of the cases sent for molecular testing. The majority of cytologically indeterminate cases sent for molecular testing were follicular-patterned lesions and their corresponding resection specimens revealed mostly low grade follicular derived neoplasms (i.e., follicular adenoma, non-invasive follicular thyroid neoplasm with papillary-like nuclear features, and follicular variant of papillary thyroid carcinoma). Of the cases with identified genetic alterations, 75% (n = 52/69) were treated surgically. In cases with no genetic alterations identified, only 18% (n = 20/109) were treated surgically. Molecular testing on cytologically indeterminate thyroid nodules can help provide a more accurate risk of malignancy assessment in patients with lesions that are difficult to diagnosis based solely on FNAC morphology. The types of genetic alterations identified in the resected thyroid lesions were consistent with what has been previously described in the literature. Additionally, we found that in the patients with indeterminate thyroid FNAC with adjunct molecular testing, more than half did not undergo surgical resection. This finding emphasizes the value of adding molecular testing in patients, particularly when attempting to reduce unnecessary surgical intervention.

Incidental 68Ga-DOTATATE uptake in thyroid nodules: Is guideline-directed management still appropriate?

BackgroundFluorodeoxyglucose uptake on positron emission tomography imaging has been shown to be an independent risk factor for malignancy in thyroid nodules. More recently, a new positron emission tomography radiotracer—Gallium-68 DOTATATE—has gained popularity as a sensitive method to detect neuroendocrine tumors. With greater availability of this imaging, incidental Gallium-68 DOTATATE uptake in the thyroid gland has increased. It is unclear whether current guideline-directed management of thyroid nodules remains appropriate in those that are Gallium-68 DOTATATE avid. MethodsWe retrospectively reviewed Gallium-68 DOTATATE positron emission tomography scans performed at our institution from 2012 to 2022. Patients with incidental focal Gallium-68 DOTATATE uptake in the thyroid gland were included. Fine needle aspiration biopsies were characterized via the Bethesda System for Reporting Thyroid Cytopathology. Bethesda III/IV nodules underwent molecular testing (ThyroSeq v3), and malignancy risk ≥50% was considered positive. ResultsIn total, 1,176 Gallium-68 DOTATATE PET scans were reviewed across 837 unique patients. Fifty-three (6.3%) patients demonstrated focal Gallium-68 DOTATATE thyroid uptake. Nine patients were imaged for known medullary thyroid cancer. Forty-four patients had incidental radiotracer uptake in the thyroid and were included in our study. Patients included in the study were predominantly female sex (75%), with an average age of 62.9 ± 13.9 years and a maximum standardized uptake value in the thyroid of 7.3 ± 5.3. Frequent indications for imaging included neuroendocrine tumors of the small bowel (n = 17), lung (n = 8), and pancreas (n = 7). Thirty-three patients underwent subsequent thyroid ultrasound. Sonographic findings warranted biopsy in 24 patients, of which 3 were lost to follow-up. Cytopathology and molecular testing results are as follows: 12 Bethesda II (57.1%), 6 Bethesda III/ThyroSeq-negative (28.6%), 1 Bethesda III/ThyroSeq-positive (4.8%), 2 Bethesda V/VI (9.5%). Four nodules were resected, revealing 2 papillary thyroid cancers, 1 neoplasm with papillary-like nuclear features, and 1 follicular adenoma. There was no difference in maximum standardized uptake value between benign and malignant nodules (7.0 ± 4.6 vs 13.1 ± 5.7, P = .106). Overall, the malignancy rate among patients with sonography and appropriate follow-up was 6.7% (2/30). Among patients with cyto- or histopathology, the malignancy rate was 9.5% (2/21). There were no incidental cases of medullary thyroid cancer. ConclusionThe malignancy rate among thyroid nodules with incidental Gallium-68 DOTATATE uptake is comparable to rates reported among thyroid nodules in the general population. Guideline-directed management of thyroid nodules remains appropriate in those with incidental Gallium-68 DOTATATE uptake.

Binary subclassification scheme (AUS-Nuclear versus AUS-Other) adequately risk-stratifies thyroid fine needle aspiration specimens classified as Atypia of Undetermined Significance

The Bethesda System for Reporting Thyroid Cytopathology previously described 4subclassesof atypia within the Atypia of Undetermined Significance (AUS) category: nuclear (AUS-Nuc), architectural (AUS-A), oncocytic (AUS-Onc), and atypia not otherwise specified (AUS-NOS). Accumulating evidence supports a binary AUS subclassification scheme based primarily on the presence of nuclear atypia only. The purpose of this study is to compare the risk stratification of binary versus 4-tier AUS subclassification systems among AUS nodules with molecular and/or histologic follow-up. Thyroid aspirates classified as AUS and tested using Afirma (Veracyte, Inc.) between 6/2013 and 7/2021 were included. For resected nodules, histological classification was considered as the final outcome. For unresected nodules, benign Afirma results were considered low-risk outcomes, similar to histologically benign nodules. Suspicious or nondiagnostic Afirma results were considered indeterminate outcomes. The prevalence of outcomes warranting surgery (noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP] or cancer) was calculated for each AUS subclass. A total of 559 AUS nodules with Afirma testing were identified. Excluding nodules with indeterminate molecular outcomes, NIFTP/cancer prevalence for AUS-Nuc was 21% (57/266), which was higher than that for AUS-A (6%, 11/188), AUS-Onc (8%, 4/53), and AUS-NOS (0%, 0/9). A binary AUS subclassification scheme based on nuclear atypia showed a significant difference in NIFTP/cancer prevalence (21% versus 6%, P < 0.0001). Binary reporting of AUS subclasses based on nuclear atypia distinguishes cases with a higher risk of NIFTP/cancer. There is a low but non-negligible prevalence of NIFTP/cancer in cases without nuclear atypia.

The Incidence Trend and Management of Thyroid Cancer-What Has Changed in the Past Years: Own Experience and Literature Review.

Because of ambiguous and widely debated observations concerning the incidence, trend, and management of TC, we performed this analysis. We drew attention to some events, such as "cancer screening activity", introduction of noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) to TC types, possibility of papillary thyroid microcarcinoma (PTMC) active surveillance (AS), occurrence of personalized medicine in TC management, and, finally, COVID-19 pandemic time. Because of the opinion that all changes have been made mostly by PTC, we compared it to the remaining types of TC in terms of incidence, clinical and pathological characteristics, and treatment. We analyzed patients treated in a single surgical center in eastern Europe (Poland). The prevalence of TC significantly increased from 5.15% in 2008 to 13.84% in 2015, and then significantly decreased to 1.33% in 2022 when the COVID-19 pandemic lasted (p < 0.0001). A similar trend was observed for PTC, when the incidence significantly increased to 13.99% in 2015 and then decreased to 1.38% in 2022 (p < 0.0001). At that time, the NIFTP category was introduced, and observation of PTMC began. The prevalence of FTC and MTC also increased until 2015 and then decreased. Significant differences in age, types of surgery, necessity of reoperation, and pTNM between PTCs and other types of TCs were observed. The average age was significantly lower in PTC patients than in patients with the remaining types of TC (p < 0.0001). Four milestones, including NIFTP introduction, the possibility of PTMC AS, personalized cancer medicine, and the COVID-19 pandemic, may have influenced the general statistics of TC.

SAT476 A Case of Thyroid Hemiagenesis

Abstract Disclosure: P. Kachhadia: None. S. Khan: None. S. Aldasouqi: None. A. Abu Limon: None. Introduction: Thyroid hemiagenesis is congenitally rare, in which one side of the thyroid does not develop. Hemiagenesis is more common with an absent left thyroid lobe, at a 4:1 ratio. Though prevalence is sited at 0.05%, actual incidence of hemiagenesis amongst the population is unknown as most patients are euthyroid and asymptomatic. We present a case of a patient who was referred to our clinic for unilateral thyroid enlargement on physical exam. Thyroid Ultrasound (US) was done which showed an absent left thyroid lobe along with enlarged right thyroid lobe and hypervascularity. There was also an incidental thyroid nodule noted on US. Case Presentation: Patient is a 38 year old female who presented to the clinic 4 years prior for enlarged thyroid nodule noted on ultrasound. With symptoms of dysphagia and a visibly enlarged gland, an US with labs was prompted by her primary physician. US showed absent left thyroid lobe and right lobe enlargement with hypervascularity and incidental subcentimeter nodule. Clinically and biochemically, the patient was euthyroid. Singular right lobe was verified on clinic real time ultrasound and on NM uptake scan. The 24 hour uptake was at 30.5%, with the upper limit of normal being 30%. With increased uptake and hypervascularity, thyroid stimulating immunoglobulin and thyrotropin receptor antibodies were checked and were not detected. It was thought that the right thyroid gland enlargement and hypervascularity were compensatory due to the left hemiagenesis. The thyroid nodule was monitored, and within 3 years of original imaging, it enlarged to 0.98 x 0.59 x 0.39 cm, with TI-RADS 5 assessment per ACR criteria. Patient chose to undergo thyroid biopsy which showed Bethesda III, Follicular Lesion of Undetermined Significance (FLUS). Microscopy showed follicular cells arranged in microfollicles and crowded groups with round, enlarged, irregular nuclei and overlapping nucleoli. Intranuclear chromatin clearing and intranuclear grooves are present. Background is hemorrhagic with minimal colloid. Molecular Thyroseq testing was at 5-10% chance of malignancy or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Genetic markers were only positive for copy number alterations. Discussion: Thyroid Hemiagenesis, though rare, has been associated with other thyroid pathologies such as hypothyroidism, hyperthyroidism and thyroid malignancies. Genetic studies have not found a common background within cases reported. As these patients are more likely to incur additional thyroid pathologies, questions still remain as to the clinical management and outcome of such patients. Due to concerning cytological features for PTC, the patient was offered right thyroidectomy and will be looking to make a decision in the near future. Presentation Date: Saturday, June 17, 2023