Machine Learning Streamlines the Morphometric Characterization and Multiclass Segmentation of Nuclei in Different Follicular Thyroid Lesions: Everything in a NUTSHELL.

The diagnostic assessment of thyroid nodules is hampered by the persistence of uncertainty in borderline cases and further complicated by the inclusion of noninvasive follicular tumor with papillary-like nuclear features (NIFTP) as a less aggressive alternative to papillary thyroid carcinoma (PTC). In this setting, computational methods might facilitate the diagnostic process by unmasking key nuclear characteristics of NIFTP. The main aims of this work were to (1) identify morphometric features of NIFTP and PTC that are interpretable for the human eye and (2) develop a deep learning model for multiclass segmentation as a support tool to reduce diagnostic variability. Our findings confirmed that nuclei in NIFTP and PTC share multiple characteristics, setting them apart from hyperplastic nodules (HP). The morphometric analysis identified 15 features that can be translated into nuclear alterations readily understandable by pathologists, such as a remarkable internuclear homogeneity for HP in contrast to a major complexity in the chromatin texture of NIFTP and to the peculiar pattern of nuclear texture variability of PTC. A few NIFTP cases with available next-generation sequencing data were also analyzed to initially explore the impact of RAS-related mutations on nuclear morphometry. Finally, a pixel-based deep learning model was trained and tested on whole-slide images of NIFTP, PTC, and HP cases. The model, named NUTSHELL (NUclei from Thyroid tumors Segmentation to Highlight Encapsulated Low-malignant Lesions), successfully detected and classified the majority of nuclei in all whole-slide image tiles, showing comparable results with already well-established pathology nuclear scores. NUTSHELL provides an immediate overview of NIFTP areas and can be used to detect microfoci of PTC within extensive glandular samples or identify lymph node metastases. NUTSHELL can be run inside WSInfer with an easy rendering in QuPath, thus facilitating the democratization of digital pathology.

Proteomics profile in encapsulated follicular patterned thyroid neoplasms.

Diagnosing encapsulated follicular-patterned thyroid tumors like Invasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma (IEFVPTC), Non-invasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP), and Well-Differentiated Tumor of Uncertain Malignant Potential (WDT-UMP) remains challenging due to their morphological and molecular similarities. This study aimed to investigate the protein distinctions among these three thyroid tumors and discover biological tumorigenesis through proteomic analysis. We employed total shotgun proteome analysis allowing to discover the quantitative expression of over 1398 proteins from 12 normal thyroid tissues, 13 IEFVPTC, 11 NIFTP, and 10 WDT-UMP. Principal component analysis revealed a distinct separation of IEFVPTC and normal tissue samples, distinguishing them from the low-risk tumor group (NIFTP and WDT-UMP). IEFVPTC exhibited the highest number of differentially expressed proteins (DEPs) compared to the other tumors. No discriminatory proteins between NIFTP and WDT-UMP were identified. Moreover, DEPs in IEFVPTC were significantly associated with thyroid tumor progression pathways. Certain hub genes linked to the response of immune checkpoint inhibitor therapy, revealing the potential predictor of prognosis. In conclusion, the proteomic profile of IEFVPTC differs from that of low-risk tumors. These findings may provide valuable insights into tumor biology and offer a basis for developing novel therapeutic strategies for follicular-patterned thyroid neoplasms.

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.

Investigation of pre-operative demographic, biochemical, sonographic and cytopathological findings in low-risk thyroid neoplasms.

OBJECTIVE: The present article analyses pre-operative demographic, biochemical, sonographic and histopathological characteristics of low-risk thyroid neoplasms (LRTNs), with a focus on four subgroups, "well-differentiated carcinoma-not otherwise specified" (WDC-NOS), "non-invasive follicular thyroid neoplasm with papillary like nuclear features" (NIFTP), "well-differentiated tumours of uncertain malignant potential" (WDT-UMP) and "follicular tumour of uncertain malignant potential" (FT-UMP). METHODS: The study retrospectively analyzed the histopathology of 2453 malignant thyroids and the final analyses included 99 cases diagnosed with LRTNs. The demographic and clinical features, pre-operative thyroid function, ultrasonography results, cytopathology results, histopathology results and prognostic classifications were assessed. RESULTS: The groups were similar demographic characteristics and the majority of clinical data, including comorbidities, thyroid function tests, thyroid cancer/neck radiotherapy history. NIFTPs represented 69.7% of all LRTNs. All (100%) WDT-UMPs had solitary nodules. Index nodule volume differed among the groups (p = .036), it was the lowest in WDC-NOS [0.68 (0.63-0.72 cc)] and highest in FT-UMP [12.6 (0.5-64 cc)]. Echogenicity findings were similar. Index nodule TIRADS demonstrated a significant difference (p = .021) but index nodule halo sign and BETHESDA scores were similar in all groups. The diameter, localisation and multicentric structure of LRTNs were again similar for all groups. Finally, prognostic scores suggested similar outcomes in all groups. CONCLUSION: The majority of LRTNs were NIFTPs in our population and all WDT-UMPs were solitary lesions. Index nodule volume was the most essential discriminating sonographic finding but further research must be performed before discriminatory potential can be described.

An investigation into noninvasive follicular thyroid neoplasms with papillary-like nuclear features: does the initial proposal on noninvasive follicular thyroid neoplasms with papillary-like nuclear features behavior hold true?

Current management of patients with noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) is lobectomy with close clinical follow-up. Because this entity is still young, we present our 5-year institutional experience with NIFTP since that time. Cases of NIFTP diagnosed from 2017 to 2022 were identified. Data points including patient demographics, radiology, cytologic and pathologic diagnoses, molecular profiles, and clinical follow-up were documented. A literature review of NIFTP case series was performed. A total of 379 cases were included (mean age: 52 years, female:male ratio 3.3:1). Ultrasound findings were available for 260 patients, and 247 underwent fine-needle aspiration (FNA). The FNA diagnoses per the Bethesda System for Reporting Thyroid Cytology were nondiagnostic (n = 2), benign (n = 16), atypia of undetermined significance/follicular lesion of undetermined significance (n = 119), follicular neoplasm/suspicious for follicular neoplasm (n = 68), suspicious for malignancy (n = 31), and malignant (n = 11). Molecular testing was performed in 179 cases. Lobectomy was performed for 183, total thyroidectomy for 192, and nodulectomy for 4 cases. The average size of NIFTP was 2.3 cm, and 232 cases had additional nodules (including benign and malignant neoplasms). Multifocal NIFTP occurred in 32 patients. Lymph nodes were evaluated in 196 cases with metastatic carcinoma in 29 cases (all with concurrent diagnoses of carcinoma). Most patients were alive at follow-up, 100 were lost to follow-up, and three died from other causes. Literature review revealed 2870 NIFTP cases with similar patient demographics and pathologic findings. We confirm that NIFTP is a low-risk neoplasm with indolent clinical behavior, which can be managed conservatively.

Serum Anti-Thyroglobulin Autoantibodies Are Specific in Predicting the Presence of Papillary-like Nuclear Features and Lymphocytic Infiltrate in the Thyroid Gland.

(1) Background: Previous studies have reported a correlation between serum anti-Thyroglobulin-antibodies (TgAb) and papillary thyroid carcinoma. The aim of our study was to evaluate whether serum TgAb and anti-thyroid-peroxidase antibody (TPO) positivity was also related to pre-neoplastic histological changes such as papillary-like nuclear features (PLNF) and with the presence of lymphocytic infiltrate (LI) in thyroid surgical specimens. (2) Methods: The study was retrospectively carried out on 70 consecutively recruited patients who underwent thyroidectomy for benign process and whose TgAb and TPOAb values were retrieved from clinical records. Histological sections of thyroid surgical samples were revised, looking for PLNF and lymphocytic infiltrate. HBME1 expression was assessed by immunohistochemistry. (3) Results: Our results showed a significant association between TgAb, PLNF, and lymphocytic infiltrate. The presence of TgAb was highly specific, but less sensitive, in predicting the presence of PLNF (sensitivity = 0.6, specificity = 0.9; positive predictive value (PPV) = 0.88; negative predictive value (NPV) = 0.63). TgAb positivity showed a good association with the presence of lymphocytic infiltrate (sensitivity = 0.62, specificity = 0.9; PPV = 0.88 and NPV = 0.68). HBME1 immunoreactivity was observed in the colloid of follicles showing PLNF and/or closely associated with LI. (4) Conclusions: The presence of PLNF and LI is associated with serum TgAb positivity. The presence of TgAb and of LI could be triggered by an altered thyroglobulin contained in the HBME1-positive colloid, and could be a first defense mechanism against PLNF that probably represent early dysplastic changes in thyrocytes.

Cytological Features of "Non-Invasive Follicular Tumour with Papillary like Nuclear Features" - A Single Institutional Experience in India.

Background: The term noninvasive follicular tumor with papillary-like nuclear features (NIFTP) was introduced as a surrogate for noninvasive encapsulated follicular variant of papillary thyroid carcinoma with a defined set of histopathologic criteria. There are very few studies depicting the cytological cues for the diagnosis of NIFTP. The objective of the study was to determine the spectrum of cytological features in fine needle aspiration cytology (FNAC) smears of cases histopathologically diagnosed as NIFTP. Methods: This was a retrospective cross-sectional study conducted over a duration of four years between January 2017 and December 2020. All surgically resected cases (n-21), who met the diagnostic criteria of NIFTP on histopathology and who underwent preoperative FNAC were included and reviewed in the study. Results: Out of a total of 21 cases, at FNAC, diagnosis of benign, suspicious for malignancy, follicular variant of papillary thyroid carcinoma, and classic papillary thyroid carcinoma (PTC) was rendered in 14 (66.6%), 2 (9.5%), 2 (9.5%), and 3 (14.28%), respectively. Scanty cellularity was noted in 12 (57.1%) cases. Papillae, sheets, and microfollicles were seen in 1 (4.7%), 10 (47.6%), and 13 (61.9%) cases, respectively. Nucleomegaly, nuclear membrane irregularities, nuclear crowding, and overlapping were seen in 7 (33.3%), 9 (42.8%), and 9 (42.8%), respectively. Nucleoli, nuclear grooving, and inclusions were seen in 3 (14.2%) 10 (47.6%), and 5 (23.8%) cases, respectively. Conclusion: At FNAC, NIFTP can be found in every category of The Bethesda System for Reporting Thyroid cytopathology (TBSRTC). Nuclear membrane irregularities, nuclear grooving, mild nuclear crowding, and overlapping were noted in a modest number of cases. However, the absence or rare occurrence of features such as papillae, inclusions, nucleoli, and metaplastic cytoplasm may help prevent an overdiagnosis of malignancy.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features: its updated diagnostic criteria, preoperative cytologic diagnoses and impact on the risk of malignancy.

Due to the extremely indolent behavior, a subset of noninvasive encapsulated follicular variant papillary thyroid carcinomas has been classified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)" since 2016 and is no longer considered carcinoma. Since the introduction of this new terminology, changes and refinements have been made in diagnostic criteria. Initially, the incidence of NIFTP was estimated substantial. However, the reported incidence of NIFTP varies greatly among studies and regions, with higher incidence in North American and European countries than in Asian countries. Thus, the changes in the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) differ inevitably among regions. Because more conservative surgery is recommended for NIFTPs, distinguishing NIFTPs from papillary thyroid carcinomas in preoperative fine-needle aspiration cytology became one of the major concerns. This review will provide comprehensive overview of updates on diagnostic criteria, actual incidence and preoperative cytologic diagnoses of NIFTP, and its impact on the ROM in TBSRTC.

Clinicopathologic Characteristics and Postsurgical Follow-Up of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features in the Postnomenclature Revision Era.

Background: Noninvasive encapsulated follicular variant papillary thyroid carcinoma (EFVPTC) was reclassified as "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) in 2016. Most existing studies that examined outcomes included patients managed as EFVPTC and only retrospectively reclassified as NIFTP. This is the first study to evaluate the clinicopathologic, molecular, and surveillance characteristics of patients diagnosed with NIFTP at the time of surgery and managed based on this diagnosis. Methods: We performed a retrospective cohort study of consecutive cases diagnosed as NIFTP from June 2016 to October 2021 identified from electronic medical records at a large tertiary care institution. Patients with coexisting low-risk thyroid cancers ≥1.0 cm in size or any size aggressive histology were excluded, and review of demographic, clinical, imaging, cytologic, and molecular genetic data was performed. Initial care was delivered according to existing clinical guidelines, with a consensus institutional plan for five-year follow-up after surgery. Results: Among 79 patients with 84 nodules diagnosed as NIFTP after surgery, 83.5% (66/79) were women and the mean age was 51 years (range, 21-84). Mean NIFTP size was 2.4 cm (range 0.15-8.0). On ultrasound, the majority of nodules were categorized as thyroid imaging, reporting and data system TI-RADS 3 (55.3%, 42/76), and TI-RADS 4 (36.8%, 28/76). On cytology, they were typically diagnosed as Bethesda III (69.1%, 47/68) or Bethesda IV (23.5%, 16/68). Molecular testing was performed on 62 nodules, and molecular alterations were found in 93.5% (58/62). The most common alterations identified in NIFTP were RAS mutation (75.4%, 43/57), THADA fusion (12.3%, 7/57), and BRAFK601E mutation (7.0%, 4/57). Fifty-two (65.8%) patients underwent lobectomy and 27 (34.2%) total thyroidectomy, and no patient received completion thyroidectomy. Twenty-one patients (26.5%) had coexisting papillary or follicular microcarcinoma. None of the patients received radioiodine ablation. On a mean follow-up of 28.5 months (range, 6-69 months), no structural or biochemical recurrences were observed. Conclusions: In this large cohort of patients with NIFTP diagnosed at the time of surgery and managed typically by lobectomy with no radioiodine ablation, no evidence of tumor recurrence was identified on a limited follow-up. This finding supports indolent clinical course of NIFTP.

Comparative BRAF V600E immunohistochemical expression in differentiated thyroid tumors with papillary features.

Differentiated thyroid tumors (DTC) are the most common indolent tumors associated with a good prognosis compared with other tumors. Its incidence during the last few decades has increased. DTC includes papillary carcinoma and follicular carcinoma. The BRAF is the most prevalent genetic mutation in thyroid carcinoma, occurring in more than 50% of papillary thyroid cancers (PTCs). The study aimed to evaluate BRAF expression in differentiated thyroid tumors with papillary-like nuclear features. Formalin-fixed paraffin-embedded blocks (FFPE) were collected from archival samples of patients in private histopathology labs in Al-Najaf city from 55 cases, which included 27 papillary thyroid carcinoma (PTC) cases, 10 cases of NIFTP, 13 FVPTC cases, 2 papillary microcarcinoma cases, and 3 NIFTP coexist with papillary microcarcinoma cases. All samples were stained using the immunohistochemistry method in the Middle Euphrates unit for cancer research at the University of Kufa/Faculty of Medicine. 15/55 (27.3%) of cases increased BRAF expression. The BRAF expression was statistically significant with tumor type (p=0.008). The higher expression was associated with 13 (48.15%) of PTC cases. However, the BRAF expression did not correlate with gender (p=0.2), tumor size (p=0.07), and tumor focality (p=0.09). BRAF V600E has prognostic value as it correlates with tumor progression.

The solid variant of papillary thyroid carcinoma: a multi-institutional retrospective study.

AIMS: The definition of papillary thyroid carcinoma, solid variant (PTC-SV) varies from >50% to 100% of solid/trabecular/insular growth (STI). We aimed to identify prognostic factors and to establish an appropriate STI cutoff for PTC-SV in this multi-institutional study of 156 PTCs with STI. RESULTS: Nodal metastases were seen in 18% and were associated with a higher percentage of papillary and STI. When substratified by infiltration/encapsulation status, the STI percentage did not impact the risk of nodal metastasis. pN1 stage was seen in 51% of infiltrative tumours and 1% of encapsulated lesions. Overall, PTC with STI had an excellent prognosis. The 10-year disease-free survival (DFS) was 87% in the entire cohort, 94% in encapsulated lesions, and 76% in infiltrative tumours. The STI percentage did not impact DFS. Fifty-four patients had noninvasive encapsulated lesions with 2-100% STI. None developed recurrence. Encapsulated lesions were enriched with RAS mutations (54%), whereas infiltrative lesions lacked RAS mutations (4%). The BRAF V600E mutation was an infrequent event, being seen in 11% of the entire cohort. CONCLUSION: In PTC with STI, the determining factor for nodal metastasis and DFS is the encapsulation/infiltration status rather than the STI percentage. Encapsulated noninvasive tumours with STI follow an indolent course with a very low risk of nodal metastasis and recurrence. Overall, PTC with STI has an excellent prognosis, with a 10-year disease-specific survival (DSS) and DFS of 96% and 87%, respectively. Therefore, the classification of SV-PTC as an aggressive PTC subtype may be reconsidered.

Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Tumour Entity with a Short History. A Review on Challenges in Our Microscopes, Molecular and Ultrasonographic Profile.

Since Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP) was introduced as a new thyroid tumour entity, many studies, and meta-analyses on diagnosing NIFTP have been published. NIFTP-revised histopathological criteria emerged in 2018. NIFTP is defined as a histological entity and its diagnosis requires a careful histological examination. Its molecular profile is similar to follicular-like tumours. Ultrasound features are unable to differentiate NIFTP. NIFTP is not a cytological diagnosis, but it influences the risk of malignancy in several categories of The Bethesda System for Reporting Thyroid Cytopathology terminology.

What you see might not be what you get: Analysis of 15 prospective cases of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

INTRODUCTION: Noninvasive follicular thyroid neoplasm with papillary-like nuclear (NIFTP) is a new entity. No previous study reported prospective cases, outlining using many quantitative and qualitative variables. METHODS: Retrospective analysis of all (15) prospective NIFTP cases diagnosed between 2017 and 2021 at our institution. Statistical quantitative analysis outlined demographic, history, ultrasound, histopathology and treatment characteristics. Qualitative analysis examined the cases, with details provided on three cases to highlight the different possible presentations and configurations. RESULTS: Mean age was 41.5 ± 9.91 years, 73.3% were females, and mean BMI was 29.49 ± 5.74 kg/m2. About 87% patients were symptomatic; 86.6% had neck swelling. Ultrasound (US) showed multiple nodules in 71.4% of cases. Fine-needle aspiration cytology (FNAC) showed that follicular lesion of undetermined significance (42.8%) was most common, followed by benign nodule (21.3%). Using the Bethesda System for Reporting Thyroid Cytopathology, 7 cases were category III, 3 category IV, 3 category II, and 1 category I. 60% of patients underwent total thyroidectomy. All cases were diagnosed postoperatively, 2 patients had additional papillary microcarcinoma. In 3 cases, the NIFTP site in the histopathology of resected specimen was different than the US-recommended site of the FNAC. CONCLUSION: We found discrepancies in the site and diagnosis of the preoperative US recommendation for the FNAC vs the postoperative histopathology of the specimen. These suggest that NIFTP might be incidentally and postoperatively diagnosed, irrespective of US or FNAC findings, hence its 'true' incidence might remain underestimated. As NIFTP cases higher BMI, Future research could predict preoperative diagnosis of NIFTP and explore associations with BMI.

What's in a Name? A Cost-Effectiveness Analysis of the Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features' Nomenclature Revision.

Background: The noninvasive subtype of encapsulated follicular variant of papillary thyroid carcinoma (eFVPTC) has been reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016 to reflect the indolent behavior and favorable prognosis of this type of tumor. This terminology change has also de-escalated its management approach from cancer treatment to a more conservative treatment strategy befitting a benign thyroid neoplasm. Objective: To characterize the reduced health care costs and improved quality of life (QOL) from management of NIFTP as a nonmalignant tumor compared with the previous management as eFVPTC. Methods: A cost-effectiveness analysis was performed by creating Markov models to simulate two management strategies for NIFTP: (i) de-escalated management of the tumor as NIFTP involving lobectomy with reduced follow-up, (ii) management of the tumor as eFVPTC involving completion thyroidectomy/radioactive iodine ablation for some patients, and follow-up recommended for carcinoma. The model was simulated for 5 and 20 years following diagnosis of NIFTP. Aggregate costs and quality-life years were measured. One-way sensitivity analysis was performed for all variables. Results: Over a five-year simulation period, de-escalated management of NIFTP had a total cost of $12,380.99 per patient while the more aggressive management of the tumor as eFVPTC had a total cost of $16,264.03 per patient (saving $3883.05 over five years). Management of NIFTP provided 5.00 quality-adjusted life years, whereas management as eFVPTC provided 4.97 quality-adjusted life years. Sensitivity analyses showed that management of NIFTP always resulted in lower costs and greater quality-adjusted life years (QALYs) over the sensitivity ranges for individual variables. De-escalated management for NIFTP is expected to produce ∼$6-42 million in cost savings over a five-year period for these patients, and incremental 54-370 QALYs of increased utility in the United States. Conclusion: The degree of cost savings and improved patient utility of de-escalated NIFTP management compared with traditional management was estimated to be $3883.05 and 0.03 QALYs per patient. We demonstrate that these findings persisted in sensitivity analysis to account for variability in recurrence rate, surveillance approaches, and other model inputs. These findings allow for greater understanding of the economic and QOL impact of the NIFTP reclassification.

Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Is Not a Cytological Diagnosis, but It Influences Cytological Diagnosis Outcomes: A Systematic Review and Meta-Analysis.

BACKGROUND: A low-risk thyroid tumour, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was introduced in 2016. NIFTP criteria require a thorough histological examination to rule out capsular and lymphovascular invasion, which denies the possibility of preoperative cytological diagnosis. Nevertheless, since the adoption of the new entity, the cytology of NIFTP has been a subject of interest. OBJECTIVES: The present systematic review and meta-analysis investigate the cytological diagnosis of NIFTP. METHOD: An online PubMed literature search was conducted between March 1, 2020, and June 30, 2020, for all original articles considering the cytology of histologically proven NIFTP. The studies including data on fine needle aspiration specimens classified by The Bethesda System for Reporting Thyroid Cytology (TBSRTC) categories, risk of malignancy (ROMs) in the TBSRTC categories, and cytomorphological features of NIFTP were included in the meta-analysis. Non-English studies and case reports were excluded. The data were tabulated and statistical analysis was performed with Open Meta-Analyst program. RESULTS: Fifty-eight studies with a total of 2,553 NIFTP cases were included in the study. The pooled prevalence of NIFTP cases was calculated among 25,892 surgically resected cases from 20 studies and the results show that NIFTP consisted 4.4% (95% confidence interval [CI]: 3.5-5.4%) of all cases. Most of the NIFTP cases (79.0%) belonged to the intermediate categories of TBSRTC. The pooled distribution of NIFTP cases in each TBSRTC category was 1.3% (95% CI: 0.8-1.7%) in non-diagnostic (ND), 8.9% (95% CI: 6.9-10.8%) in benign, 29.2% (95% CI: 25.0-33.4%) in atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS), 24.2% (95% CI: 19.6-28.9%) in follicular neoplasm (FN), 19.5% (95% CI: 16.1-22.9%) in suspicious for malignancy (SM), and 6.9% (95% CI: 5.2-8.7%) in malignant. Compared to pre-NIFTP era, the pooled risk differences of ROM were reduced by 2.4% in ND, 2.7% in benign, 8.2% in AUS/FLUS, 8.2% in FN, 7.3% in SM, and 1.1% in the malignant category. The cytomorphological features of NIFTP were similar to follicular variant of papillary thyroid carcinoma (FVPTC) but lesser to papillary thyroid carcinoma (PTC). CONCLUSIONS: Based on our results, NIFTP remains a histological diagnosis. Although cytomorphological features cannot be used in differentiating NIFTP from FVPTC, they may guide in separating NIFTP from PTC. Features such as papillae, microfollicles, giant cells, psammoma bodies, and the amount of papillary-like nuclear features should be taken into account when suspicious of NIFTP. NIFTP should not have papillae or psammoma bodies, and giant cells were rarely observed.

Impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features on fine-needle aspiration diagnoses of thyroid nodules.

In 2016, the entity of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was proposed. This study investigated the impact of NIFTP nomenclature on fine-needle aspiration (FNA) evaluation of thyroid nodules and clinical management, as well as the molecular profile of NIFTP. The study included 23 out of 275 cases diagnosed as follicular variant papillary thyroid carcinoma from 2005 to 2015 that were reclassified as NIFTP, as well as 14 cases with an original diagnosis of NIFTP from 2016 to 2019. Information on demographic characteristics, FNA diagnoses, and follow-up was collected. Before 2016, 43.5% of NIFTP surgical cases were diagnosed as malignant or suspicious for malignancy by presurgical FNA, 80% of which received total thyroidectomy. Since 2016, only 15.4% of NIFTP cases were diagnosed as malignant or suspicious for malignancy and treated with total thyroidectomy. The overall total thyroidectomy rate decreased from 56.5% to 21.4% for NIFTP cases. RAS mutations (KRASQ61R and NRASQ61R ) were present in 57.1% of NIFTP cases, with no BRAF mutations identified. Our study demonstrates a significant impact of NIFTP nomenclature on FNA diagnosis of thyroid nodules with reduced diagnoses as malignant or suspicious for malignancy, thus avoiding overdiagnosis and overtreatment of NIFTP patients. The molecular study indicates that RAS mutations play an important role in NIFTP tumorigenesis.

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.

Pathological findings of the retrospective diagnosis of NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) in 84 cases from Turkey and systematic review.

AIM: The terminology of "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was introduced in 2016; and estimated to cause significant effects in the clinical management of thyroid nodules. The aim of our study is to review our cases that were previously diagnosed as non-invasive encapsulated follicular variant PTC (NI/E-FVPTC) which are compatible with NIFTP and to correlate their follow-up. METHOD: All thyroidectomy cases evaluated in the last 15 years were screened, and possible NIFTP cases were determined among patients with NI/E-FVPTC and they were re-examined microscopically. Revised histopathological criteria were used for the retrospective diagnosis of NIFTP. Histopathological findings were correlated to follow up information. RESULTS: Totally 2138 cases had been previously diagnosed with PTC; 481 (22.5%) of them were FVPTC. After microscopic reevaluation of potential NIFTP cases, 84 cases (3.9%) received final diagnosis of NIFTP. 78.6% of NIFTP patients were female (F/M: 66/18); mean age was 49.0, tumor diameter was 22.7 mm and follow-up time was 66.4 months. 17.9% of NIFTP cases were multifocal and 13.1% were bilateral. No recurrence, lymph node involvement or distant metastasis was detected in any of the patients who were followed up. The mean age of the patients who had total thyroidectomy and received RAI was significantly higher than those who did not. CONCLUSION: Although conservative treatment of NIFTP with lobectomy is recommended, age of the patients has been continuing to be the most important determinant for the clinicians to decide on total thyroidectomy and RAI ablation therapy at our institution.

Revised Bethesda System for Reporting Thyroid Cytology: Lessons learned from an appraisal of 5 years of experience in a central hospital.

OBJECTIVE: The Bethesda System for Reporting Thyroid Cytology (BSFRTC) is widely adopted in the management of thyroid nodules. The system was updated in 2017, and its impact is the subject of this paper. METHODS: All thyroid fine needle aspirations from 2016-2020 using the BSFRTC, with follow-up surgical pathology, were reviewed. The risk of neoplasia (RON), risk of malignancy (ROM), RON/ROM ratio, and surgical follow-up rate were determined for each diagnostic category with cytohistological correlation. ROM was calculated in two separate manners, with non-invasive follicular tumours with papillary-like nuclear features (NIFTP) counted as malignant or non-malignant. Sensitivity, specificity, negative and positive predictive values were determined for indeterminate categories: atypia of undetermined significance (AUS), suspicious for follicular neoplasm (SFN), and suspicious for malignancy (SFM). RESULTS: RON, ROM, and the surgical follow-up rate increased steadily from the benign through intermediate to malignant categories. The omission of NIFTP from malignant lesions reduced the calculated ROM in indeterminate categories and improved the stratification between AUS and SFN. ROM in AUS was distinct from SFN. AUS has a well-balanced sensitivity and specificity favouring a screening rather than a diagnostic category. The calculated RON/ROM was significantly higher in AUS (1.56), compared to SFN (1.03) and SM (1.05), in agreement with current BSRTC management recommendations. CONCLUSIONS: AUS is an important screening category and should remain with the addition of subcategorisation. RON and surgical follow-up rates are essential quality indicators. The RON/ROM ratio could be utilised to determine appropriate management for each diagnostic category on an institutional basis.