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Background: 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. Methods: 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. Results: 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). Conclusion: NIFTPs have heterogeneous presentation according to TIRADSs with very low indication rate for FNA. [ABSTRACT FROM AUTHOR]

The classification of thyroid nodules, particularly those with a follicular growth pattern, has significantly evolved. These tumors, enriched with RAS or RAS-like mutations, remain challenging for pathologists due to variables such as nuclear atypia, invasion, mitotic activity, and tumor necrosis. This review addresses the histological correlates of benign, low-risk, and malignant RAS-mutant thyroid tumors, as well as some difficult-to-classify follicular nodules with worrisome features. One prototypical RAS-mutant nodule is non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The assessment of nuclear characteristics in encapsulated/well-demarcated non-invasive RAS-mutant follicular-patterned tumors helps distinguish between follicular thyroid adenoma (FTA) and NIFTP. Despite this straightforward concept, questions about the degree of nuclear atypia necessary for the diagnosis of NIFTP are common in clinical practice. The nomenclature of follicular nodules lacking clear invasive features with increased mitotic activity, tumor necrosis, and/or high-risk mutations (e.g., TERT promoter or TP53) remains debated. Invasion, particularly angioinvasion, is the current hallmark of malignancy in RAS-mutant follicular-patterned neoplasms, with follicular thyroid carcinoma (FTC) as the model. Assessing the tumor interface is critical, though full capsule evaluation can be challenging. Multiple levels and NRASQ61R-specific immunohistochemistry can aid in identifying invasion. Controversies around vascular invasion persist, with ancillary stains like CD31, ERG, and CD61 aiding in its evaluation. Moreover, the review highlights that invasive encapsulated follicular variant papillary thyroid carcinoma (IEFVPTC) is closely associated with FTC, suggesting the need for better nomenclature. The concept of "high-grade" differentiated carcinomas, applicable to FTC or IEFVPTC with necrosis and/or high mitotic activity, is also discussed. [ABSTRACT FROM AUTHOR]

The term noninvasive tumor with a follicular growth pattern and nuclear features of papillary thyroid cancer (NIFTP) is used to describe a tumor currently considered as a pre-malignant lesion for which a conservative therapeutic approach (i.e., lobectomy without radioiodine therapy) is strongly suggested. However, some patients with NIFTP and loco-regional or distant metastases have been already reported. We present an adult male patient with a final histological diagnosis of NIFTP and lymph node metastasis noted at post-therapy whole-body scintigraphy performed some days after radioiodine therapy. [ABSTRACT FROM AUTHOR]

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a low-risk thyroid tumor with a favorable prognosis. Nonetheless, differentiating NIFTP from other thyroid tumors remains challenging, necessitating reliable diagnostic markers. This study is aimed at discovering NIFTP-specific mRNA markers through RNA sequencing analysis of thyroid tumor tissues. We performed mRNA expression profiling for 74 fresh frozen thyroid tissue samples, including NIFTP and benign and malignant follicular-cell-derived tumors. NIFTP/malignant tumors showed 255 downregulated genes and 737 upregulated genes compared to benign tumors. Venn diagram analysis revealed 19 significantly upregulated and 7 downregulated mRNAs in NIFTP. Akaike information criterion analysis allowed us to select OCLN, ZNF423, LYG1, and AQP5 mRNA markers. We subsequently developed a predictive model based on logistic regression analysis using these four mRNAs, which we validated in independent samples (n = 90) using a qRT-PCR assay. This model demonstrated high accuracy in predicting NIFTP in discovery dataset (AUC (area under the receiver operating characteristic) = 0.960) and the validation dataset (AUC = 0.757). Our results suggest that OCLN, ZNF423, LYG1, and AQP5 mRNA markers might serve as reliable molecular markers for identifying NIFTP among other thyroid tumors, ultimately aiding in accurate diagnosis and management of NIFTP patients. [ABSTRACT FROM AUTHOR]

There is no accepted consensus or algorithm for the preoperative diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in patients with thyroid nodules. In this study, we evaluated the importance of preoperative neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in the differential diagnosis of NIFTP. Pathology preparations of 209 patients with a follicular variant of papillary thyroid carcinoma (FVPTC) diagnosed after thyroid surgery in a tertiary health center between January 2010 and January 2020 were re-evaluated. Patients were divided into NIFTP and encapsulated follicular variant papillary thyroid carcinoma (EFVPTC) to compare. Of the patients, 58 (27.7%) were NIFTP, and 151 (72.3%) were EFVPTC. There was no statistically significant difference in terms of age (p = 0.46), tumor size (p = 0.51), gender (p = 0.48), and surgical technique (p = 0.78) between the groups. The probability of the neutrophil-to-lymphocyte ratio (NLR) > 2 is more common in the EFVPTC group. It was statistically significant that the NIFTP group was 1.96 times more likely to have NLR > 2 (OR: 1.96, 95% CI: 1.06–3.63) (p < 0.05). However, there was no risk difference between the groups in terms of the platelet-to-lymphocyte ratio (PLR) (OR: 0.76, 95% CI: 0.41–1.43) (p > 0.05). The diagnosis of NIFTP should be kept in mind in the evaluation of patients whose thyroid fine-needle aspiration (FNA) biopsy results are in the intermediate group. NIFTP exhibits better prognostic findings than classic thyroid papillary cancer and EFVPTC. Therefore, preoperative diagnosis of NIFTP in line with laboratory, ultrasonography, and FNA findings will save the patient from unnecessary overtreatment. [ABSTRACT FROM AUTHOR]

Differentiated thyroid carcinoma is one of the commonest malignancies in head and neck region. Among differentiated thyroid carcinoma, papillary carcinoma is the commonest. Encapsulated follicular variant of papillary thyroid carcinoma tumors are very indolent tumors which behave like benign tumors. Many tumors have been over diagnosed and over treated in spite of their indolent nature. We aimed to find out if total thyroidectomy is really required for very low grade tumors like encapsulated FVPTC. We operated 672 patients of thyroid disease during 2012 to 2020 in SMS Medical College, Jaipur. Out of 256 patients, 199 patients (78%) had papillary carcinoma of thyroid. Classical variant was present in 40% and follicular variant was present in 35% (N—69). Out of 69 patients with follicular variant of PTC, 59 patients had well encapsulated type of follicular variant of PTC while 10 patients had invasive type of follicular variant of PTC. Encapsulated FVPTC are less aggressive and indolent tumors. They should be treated more conservatively. Hemithyroidectomy is sufficient treatment for its complete cure. Out of 69 patients with Follicular variant of PTC, 59 patients had encapsulated disease. Out of 59 patients, 14 (24%) had bilateral nodular disease. 45 (77%) patients had unilateral disease; multicentric in one lobe in 9 (15%) patients and unicentric in 36 (61%) patients. However, encapsulated FVPTC was only found in predominant lobe and the non dominant lobe had benign disease. [ABSTRACT FROM AUTHOR]

Purpose: Non-invasive encapsulated follicular variant of papillary thyroid cancer was reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). These neoplasms have an extremely low malignant potential. The aim of this study was (1) to assess the prevalence of NIFTP in patients with papillary thyroid carcinoma, (2) to evaluate their outcomes, and (3) to determine their molecular profile. Methods: Multicenter, descriptive, retrospective study. Patients with papillary thyroid cancer diagnosed from January 2006 to December 2016 from 11 referral centers were included. Diagnosis of NIFTP was based on criteria described by Nikiforov et al. in 2018. At least two pathologists agreed on the diagnosis. Two thousand six hundred and seventy-seven papillary thyroid cancer patients were included; 456 (17%) of them were follicular variant papillary thyroid cancer, and 30 (1.12%) fulfilled diagnostic criteria for NIFTP. Results: Each of the 30 included patients underwent a total thyroidectomy, and 50% were treated with radioiodine (median dose 100 mCi). After a median follow-up of 37 months, 84% of patients had an excellent response, 3% had an indeterminate response and data was missing in the remaining 13%. No metastatic lymph nodes, distant metastases or recurrences were found. RAS mutations were detected in 4 patients (13%). Conclusion: The prevalence of NIFTP in our series is amongst the lowest reported. Excellent outcomes of patients underscore their low malignant potential. Molecular findings differ from other series, probably related to environmental or ethnic features of our population and the meticulous criteria for diagnosing NIFTP. [ABSTRACT FROM AUTHOR]

Purpose: To determine the rate of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in a multi-institutional series from the Iberian Peninsula and describing this NIFTP cohort. Methods: Retrospective study of papillary thyroid carcinoma (PTC) or well-differentiated tumours of uncertain malignant potential (WDT-UMP) diagnosed between 2005 and 2015 and measuring ≥5 mm in adult patients from 17 hospitals. Pathological reports were reviewed to determine the cases that fulfil the original criteria of NIFTP and histology was reassessed. Rates were correlated with the number of PTC and its follicular variant (FVPTC) of each institution. Demographic data, histology, management, and follow-up of the reclassified NIFTP cohort were recorded. Results: A total of 182 cases with NIFTP criteria were identified: 174/3372 PTC (rate: 5.2%; range: 0–12.1%) and 8/19 WDT-UMP (42.1%). NIFTP rate showed linear correlation with total PTC (p: 0.03) and FVPTC (p: 0.007) identified at each centre. Ultrasound findings were non-suspicious in 60.1%. Fine-needle cytology or core biopsy diagnoses were undetermined in 49.7%. Most patients were treated with total thyroidectomy. No case had nodal disease. Among patients with total thyroidectomy, 89.7% had an excellent response evaluated 1 year after surgery. There were no structural persistence or relapses. Five patients showed residual thyroglobulin after 90 months of mean follow-up. Conclusions: NIFTP rate is low but highly variable in neighbouring institutions of the Iberian Peninsula. This study suggests pathologist's interpretation of nuclear alterations as the main cause of these differences. Patients disclosed an excellent outcome, even without using the strictest criteria. [ABSTRACT FROM AUTHOR]

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The thyroid is an unusual site for metastasis, and metastases in a preexisting primary thyroid tumor are exceedingly rare. We report the first case of a patient with colon cancer who was diagnosed with a thyroid metastasis in a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). A 55-year-old male patient presented with a 19 mm thyroid nodule in the inferior left lobe. It was EU-TIRADS 5 on echography and suspicious of papillary thyroid carcinoma (Bethesda V) on cytology. Macroscopically, the nodule was fleshy and completely encapsulated. At frozen section examination, it demonstrated follicular architecture with mild atypia. Inside the nodule was a focus of tumor with glandular architecture, marked cellular atypia, and necrosis. These findings suggested a secondary malignancy. The patient's medical history was significant for metastatic colon cancer. The definitive histology showed features of metastatic colorectal adenocarcinoma within a NIFTP. Immunohistochemical studies were confirmatory with expression of CDX2 and CK20 localized to the metastatic focus. PAX8, TG, and TTF were negative in the metastasis but expressed in the surrounding NIFTP lesion. The possibility of a metastasis to the thyroid may be considered in patients presenting with a solitary thyroid nodule with a previous history of cancer. Metastatic colorectal adenocarcinoma occurring in a NIFTP has never been reported before now, although metastases to the thyroid are documented in the literature. In cases of a secondary malignancy to the thyroid, treatment is controversial. [ABSTRACT FROM AUTHOR]

Objective: Noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) is the term to describe what was previously known as encapsulated follicular variant of papillary thyroid carcinoma. This new paradigm shift was agreed upon by experts in the field. The objective of this study is to evaluate cases previously diagnosed as follicular adenomas, follicular variant of papillary thyroid carcinoma and hyperplastic nodules to be reclassified as NIFTP according to the new criteria. Furthermore, the clinical follow-up of these NIFTP cases is evaluated. Methods: This retrospective study reviewed potential NIFTP cases over the last 13 years, at Jordan University Hospital. Results: A total of 811 thyroid surgery reports were identified and revised to identify the potential NIFTP cases. The review yielded 173 cases identified as potential NIFTP cases. Further pathological slide review resulted in a revised diagnosis of 32 cases of NIFTP according to the new criteria. The NIFTP cases comprised 4% of the total number of thyroidectomy cases and 16.1% of the total pool of previously diagnosed papillary thyroid carcinoma cases at our institution. While 111 cases retained their original diagnosis. Follow-up showed that all patients are alive and well with no evidence of disease. Conclusion: Patients with NIFTP are not uncommon and the diagnosis is made only after a thorough evaluation of excision. Therefore, initial conservative management of solitary thyroid nodules suspicious for NIFTP in the form of lobectomy is recommended to avoid unnecessary total thyroidectomies. Our follow-up of NIFTP cases is similar to all previous reports. [ABSTRACT FROM AUTHOR]

The recently adopted terminology of "Noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) reflects the indolent behavior of these tumors. In contrast to conventional papillary thyroid carcinomas, NIFTP can be managed conservatively. The purpose of this study was to investigate changes in surgical and pathologic practice patterns at our institution since the introduction of the NIFTP diagnosis in 2016. A retrospective analysis of all thyroid specimens received in our laboratory between January 2015 and April 2017 was performed. The final cohort consisted of 1508 thyroidectomy specimens from 1508 patients (1153 (76.5%) women and 355 (23.5%) men), of which 1011 (67%) were total thyroidectomies and 497 (33%) were partial thyroidectomies. There were 558 (69.2%) total thyroidectomies and 248 (30.8%) partial thyroidectomies performed prior to introduction of the NIFTP diagnosis and 453 (64.5%) and 249 (35.5%) total and partial thyroidectomies, respectively, after the change in nomenclature. Within a year following the initial use of this diagnosis, 67 NIFTP cases were identified (9.5% of all thyroidectomies), whereas compared with the year preceding it, malignant diagnoses decreased from 54.5 (439) to 44.6% (313), and the benign category remained unchanged from 44.5 (367) to 45.9% (322). For the entirely submitted 67 NIFTP cases, the mean number of blocks submitted was 14.7 (0.98 blocks/g); for malignant lesions 17.7 (0.92 blocks/g); and for benign lesions 16.6 (0.75 blocks/g). The results of our study suggest that NIFTP are encountered in almost 10% of thyroidectomies at our institution with expected shifts in cytology and surgical pathology diagnoses as a result of the change in nomenclature. During this time period, significant shifts towards less aggressive surgical management were not observed. All 67 NIFTP nodules were submitted entirely with no significant difference in the number of cassettes submitted for NIFTP nodules as compared with follicular variant papillary thyroid carcinoma (PTC), classic variant PTC, or follicular adenoma. [ABSTRACT FROM AUTHOR]

Purpose: Our study aimed to describe the evolution of the rate of pathological subtypes of well-differentiated follicular-cell derived thyroid carcinomas (DTCs) in the Department of Pathology, Emergency County Hospital Targu-Mures, Romania over a 15 year period and to assess the impact the new 2017 WHO and TNM classifications of thyroid tumors had on our cases. Methods: The pathological data were retrieved from the original pathological reports. After applying the exclusion criteria the remaining cases were reviewed on a double-headed microscope and reclassified according to the 2017 WHO and TNM staging system. The follow-up data were collected from the Institute of Oncology Cluj-Napoca, Romania. Results: Our study included 396 cases of DTCs (375 papillary, 11 follicular, and 10 Hürthle cell carcinomas). PTCs revealed a significant increasing trend over the study period, whereas follicular and Hurthle cell carcinomas remain rare; 125/131 of noninvasive encapsulated follicular variant PTC (EFVPTC) were reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), resulting in a 33.3% reduction in the number of PTCs. According to 2017 TNM stage-grouping 31% of 271 patients with DTC were downstaged. Follow-up data were available for most of the patients (65.7%, mean period 58.1 months). All patients with noninvasive EFVPTC were disease free at the last clinical assessment. Conclusions: The increasing rate of PTC was maintained even after exclusion of NIFTP. By applying 2017 TNM criteria, a significant number of DTC cases were downstaged into a more favorable group. Follow-up data highlight the indolent behavior of noninvasive EFVPTCs reclassified as NIFTPs. [ABSTRACT FROM AUTHOR]

The renaming of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was proposed by a group of experts in 2016 to prevent overtreatment of indolent, low-risk thyroid cancers. The aim of this study was to estimate the incidence and outcome for patients meeting the NIFTP criteria in a well-defined geographic region. Our cohort consisted of 134 patients with papillary thyroid carcinoma from the Region of Southern Denmark (RSD), 2007 to 2011. Patients were retrieved from the Danish Thyroid Cancer (DATHYRCA) Database. All potential NIFTP cases were reviewed by a thyroid pathologist. We identified no cases meeting all diagnostic criteria, but one probable NIFTP case from 2007 to 2011. The patient was treated according to the national guidelines and is alive and recurrence-free after 106 months of follow-up. Molecular testing showed KRAS mutation. In a population based set up the incidence rate of NIFTP is very low. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: The nomenclature "Non-invasive Follicular Neoplasm with Papillary-like Nuclear Features (NIFTP)" was introduced in 2016. While NIFTP differs from classic papillary thyroid carcinoma (PTC) in imaging, cytomorphology, histology, molecular profile, treatment, follow up, outcome, and behavior, it largely overlaps with follicular variant of PTC at imaging and cytomorphology. Herein, we review the literature for better understanding NIFTP, and its impact on patient care. Methods: The English literature was thoroughly evaluated with the key word of "Noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP)". Observations: NIFTP presents as a thyroid nodule. On imaging, it is a round-to-oval, well circumscribed mass with solid internal content. Aspirated material shows a microfollicular pattern with focal nuclear features of PTC mostly reported in categories 3–5 of the Bethesda System for Reporting Thyroid Cytology (TBRSTC). NIFTP has decreased risk of malignancy in TBRSTC categories 3–6. Histologic examination of NIFTP reveals an encapsulated neoplasm with follicular pattern and nuclear features of PTC with no capsular or vascular invasion. No papillary structure, atypia, or mitosis is present. In contrast to PTC, only 4% of NIFTP cases harbor a BRAF mutation. Because NIFTP carries an excellent prognosis and indolent behavior, the tumor behavior was changed from malignant to a neoplasm with tumor with extremely indolent behavior. The recommended treatment is lobectomy with no further ablation therapy. Until better understanding of NIFTP, patient's follow up should be occasionally performed by neck ultrasonography and serum thyroglobulin measurement. Conclusion: NIFTP carries an excellent prognosis. It is critical for both clinicians and patients to be aware of extremely indolent behavior of NIFTP in order to prevent unnecessary, aggressive treatment. Highlights: Non-invasive follicular thyroid neoplasm with papillary like nuclear features (NIFTP) refers to a subset of encapsulated thyroid neoplasms that was recently reclassified from malignant to tumor with extremely indolent behavior. The tumor behavior and molecular profile differ from papillary thyroid carcinoma and it is treated with lobectomy with a favorable outcome. [ABSTRACT FROM AUTHOR]

Advances in our understanding of thyroid lesions, especially those entities with an indolent behavior, has led clinicians to question the most appropriate surgical management of such thyroid nodules. Several studies have shown that the non-invasive encapsulated follicular variant of papillary thyroid carcinomas (NI-EFVPC) exhibits poor histopathologic diagnostic reproducibility and have been over-treated as conventional thyroid cancer. In 2015, an international thyroid working group re-evaluated NI-EFVPC and its diagnostic criteria. The new terminology of "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was accordingly introduced to replace NI-EFVPC. The literature has emphasized that NIFTPs are biologically similar to follicular adenomas lacking lymph node metastases and/or recurrence. While the definition of NIFTP is based on specific morphological parameters, recent studies have questioned whether the criterion allowing less than 1% of true papillae should be revised to a total absence of papillae. The motivation for this revision is the rare finding, in some studies, of lymph nodes with metastatic NIFTP. This review evaluates the existing published series of NIFTP cases, clinical consequences of NIFTP, and emerging changes in the diagnostic criteria for NIFTP. The introduction of NIFTP has resulted in significant impact on the clinical management of thyroid nodules. Recent revisions in the morphological criteria for NIFTP emphasize the need to adhere to very stringent histomorphologic criteria when making a diagnosis of NIFTP. The adoption of NIFTP terminology instead of NI-EFVPC is associated with conservative lobectomy without radioactive iodine treatment in the majority of cases. [ABSTRACT FROM AUTHOR]

Papillary thyroid carcinoma (PTC) is defined by an invasive growth pattern and classic nuclear features: enlarged, grooved, overlapping nuclei with chromatin clearing and intranuclear cytoplasmic pseudoinclusions (INCP). True INCPs are characteristic of PTC, but may infrequently be seen in noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP). Nuclear abnormalities that mimic INCP (“pseudo-pseudoinclusions”) are common in a variety of thyroid lesions. H&E and ubiquitin-stained whole tissue sections of classic PTC (n = 25) and NIFTP (n = 35) were evaluated. On H&E, true INCPs were present in all (100%) PTCs and absent in all NIFTPs (0%). Pseudo-pseudoinclusions were present in 13 (37%) NIFTPs. In 24 (96%) PTCs, ubiquitin was strongly expressed within INCPs. In NIFTPs, optically clear nuclei or pseudo-pseudoinclusions did not express ubiquitin (0/35). Occasionally, nuclear vacuoles in NIFTP demonstrated a marginated staining pattern, in which strong ubiquitin expression was seen at the periphery of the nucleus, but the central pale area was negative. In addition, 2 NIFTPs demonstrated intrafollicular psammomatoid calcifications which were strongly ubiquitin-positive. Psammoma bodies in PTC were ubiquitin-negative in the majority of cases. We report a previously undescribed finding: strong ubiquitin expression in true INCPs in PTC, absence of true INCPs in NIFTP, and absence of ubiquitin expression in pseudo-pseudoinclusions in NIFTP. This finding supports the difference between true INCPs (found only in PTC) and pseudo-pseudoinclusions (found in NIFTP). Using strict histologic criteria and ubiquitin immunostaining, the presence of true pseudoinclusions may exclude a diagnosis of NIFTP. Caution should be exercised when interpreting nuclear vacuoles or pseudo-pseudoinclusions. [ABSTRACT FROM AUTHOR]

The Bethesda System for reporting thyroid cytopathology (BSRTC) predicts an incidence of malignancy of less than 5% in thyroid nodules with a benign diagnosis on fine-needle aspiration (FNA). However, recent series have suggested that the true rate of malignancy might be significantly higher in this category of patients. We reviewed our experience by performing a retrospective analysis of patients with benign thyroid FNA results who underwent thyroidectomy between 2008 and 2013 at a large academic center. Information including demographics, ultrasound features, FNA diagnosis, and surgical follow-up information were recorded. Slides were reviewed on cytology-histology discrepant cases, and it was determined whether the discrepancy was due to sampling or interpretation error. A total of 802 FNA cases with a benign diagnosis and surgical follow-up were identified. FNA diagnoses included 738 cases of benign goiter and 64 cases of lymphocytic thyroiditis. On subsequent surgical resection, 144 cases were found to be neoplastic, including 117 malignant cases. False negative, defined as interpretation error and inadequate biopsy of the nodule harboring malignancy, was 6%. When cases of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were excluded from the analysis, false-negative rate was 5%. When microPTC cases were excluded, false-negative rate was 3% and was slightly less than 3% when both microPTC and NIFTP cases were excluded from the analysis. Retrospective review of neoplastic cases showed that 57% were due to sampling error and 43% were due to interpretation error. Interpretation error was more likely to occur in follicular patterned neoplasms (75%), while sampling error was more common in non-follicular variants of papillary thyroid carcinoma (non-FVPTC) (61%). With the exclusion of microPTC, interpretation errors were still more likely to occur in follicular neoplasms (79%) but there was no significant difference in sampling error between non-FVPTC (37%) and follicular patterned neoplasms (42%). Tumor size was larger in cases with interpretation error (mean = 2.3 cm) compared to cases with sampling error (mean = 1.4 cm). This study shows that the false-negative rate of thyroid FNA at our institution is not significantly above the rate suggested by the BSRTC. Interpretation errors were more likely to occur in follicular patterned neoplasms, while non-FVPTC was more frequently found in false negative cases due to inadequate sampling. [ABSTRACT FROM AUTHOR]

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was initiated and promoted by pathologists. Recent Asian studies added new knowledge to the existing literature to aid a better understanding of NIFTP. Our original data and the results of a meta-analysis suggest that the initial rate of NIFTP has been overestimated, averaging 9.1% (95% confidence interval [CI] 6.0-12.7%) of all papillary thyroid cancers worldwide. The incidence of NIFTP in the Asian population (1.6%, 95% CI 0.9-2.5%; 7 studies) is significantly lower than that reported in the non-Asian series (13.3%, 95% CI 9.0-18.3%; 18 studies). Such difference could be attributed to various perceptions of histological diagnostic thresholds, different nature of papillary thyroid carcinoma, and different approaches in the management of thyroid nodules. The active surveillance for indeterminate nodules and NIFTP, largely represented in the indeterminate cytologic categories, promoted by Japanese institutions establishes a new paradigm to reduce overtreatment of these patients. The lower prevalence of NIFTP in the Asian series indicates a low impact on the risk of malignancy in cytopathology, as it was demonstrated in our original multi-institutional cohort of thyroid nodules, and may predict a low impact on the performance of commercial molecular tests. Several Korean studies addressed the issue of BRAF mutation in NIFTP, which prompted the current refinement of the diagnostic criteria for NIFTP. Our survey of Asian pathologists found that the term NIFTP has not been universally adopted in the local practice. Endocrine pathologists must promote the new entity through provision of educational activities. [ABSTRACT FROM AUTHOR]

Purpose: Thyroid nodules are of common occurrence in the general population. About a fourth of these nodules are indeterminate on aspiration cytology placing many a patient at risk of unwanted surgery. The purpose of this review is to discuss various molecular markers described to date and place their role in proper perspective. This review covers the fundamental role of the signaling pathways and genetic changes involved in thyroid carcinogenesis. The current literature on the prognostic significance of these markers is also described.Methods: PubMed was used to search relevant articles. The key terms “thyroid nodules”, “thyroid cancer papillary”, “carcinoma papillary follicular”, “carcinoma papillary”, “adenocarcinoma follicular” were searched in MeSH, and “molecular markers”, “molecular testing”, mutation, BRAF, RAS, RET/PTC, PAX 8, miRNA, NIFTP in title and abstract fields. Multiple combinations were done and a group of experts in the subject from the International Head and Neck Scientific Group extracted the relevant articles and formulated the review.Results: There has been considerable progress in the understanding of thyroid carcinogenesis and the emergence of numerous molecular markers in the recent years with potential to be used in the diagnostic algorithm of these nodules. However, their precise role in routine clinical practice continues to be a contentious issue. Majority of the studies in this context are retrospective and impact of these mutations is not independent of other prognostic factors making the interpretation difficult.Conclusion: The prevalence of these mutations in thyroid nodule is high and it is a continuously evolving field. Clinicians should stay informed as recommendation on the use of these markers is expected to evolve. [ABSTRACT FROM AUTHOR]

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an indolent thyroid tumor characterized by frequent RAS mutations and an absence of the BRAF V600E mutation commonly seen in classical papillary thyroid carcinoma (cPTC). The ability to differentiate potential NIFTP/follicular variant of papillary thyroid carcinoma (FVPTC) from cPTC at the time of fine-needle aspiration (FNA) can facilitate conservative management of NIFTP. The aim of the current study was to investigate how molecular testing may add to cytologic assessment in the pre-operative differentiation of potential NIFTP/FVPTC and cPTC. We had previously evaluated cytologists’ ability to prospectively distinguish potential NIFTP/FVPTC from cPTC in a cohort of 56 consecutive FNAs diagnosed as malignant or suspicious for malignancy. We utilized this cohort to perform molecular analysis. Detected molecular abnormalities were stratified into two groups: (1) those supporting malignancy and (2) those supporting a diagnosis of potential NIFTP/FVPTC. The cytologists’ characterization of cases and the detected molecular alterations were correlated with the final histologic diagnoses. Molecular testing was performed in 52 (93%) of the 56 cases. For the 37 cases cytologists favored to be cPTC, 31 (84%) had a molecular result that supported malignancy (28 BRAF V600E mutations, 2 NTRK1 fusions, 1 AGK-BRAF fusion). For the 8 cases that were favored to be NIFTP/FVPTC by cytologists, 7 (88%) had a molecular result that supported conservative management (1 NRAS mutation, 6 wild-type result). Seven cases were designated as cytomorphologically indeterminate for NIFTP/FVPTC or cPTC, of which 6 (86%) had a molecular result that would have aided in the pre-operative assessment of potential NIFTP/FVPTC or cPTC/malignancy. These included 3 BRAF V600E mutations in nodules that were cPTC on resection, an HRAS mutation, and a wild-type result in the 2 nodules that were NIFTP, and a TERT promoter mutation along with an NRAS mutation in a poorly differentiated thyroid carcinoma. For nodules with an FNA diagnosis of suspicious for malignancy or malignant, cytologists can differentiate most cases of potential NIFTP/FVPTC from cPTC. However, molecular testing may be valuable for a subset of cases, especially those that are indeterminate for potential NIFTP/FVPTC versus cPTC based on cytologic features alone. [ABSTRACT FROM AUTHOR]

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed as a designation for a subset of follicular variant papillary thyroid carcinoma (FVPTC). Encapsulated FVPTC has been shown to be a fairly indolent tumor, and NIFTP are expected to represent the most indolent subset of these tumors. Many of the exclusion criteria for NIFTP related to architecture and a lack of psammoma bodies are designed to preclude the inclusion of more aggressive non-FVPTC tumors in this indolent group and also exclude the diagnosis of FVPTC. In addition to strict application of histologic features to ensure that NIFTP represents a subset of encapsulated FVPTC without invasion, other exclusion criteria including high mitotic activity and necrosis may also lead to a lack of one-to-one correlation between the diagnosis of NIFTP and encapsulated FVPTC without invasion. In this series, 50 cases previously diagnosed as FVPTC over a 2-year period from a large academic center are retrospectively reviewed for reclassification as NIFTP. Additionally, cases not meeting criteria for NIFTP are more accurately classified using the most up to date WHO criteria. Prior BRAF V600E mutation testing was examined for these tumors when available. Seventeen of 50 (34%) tumors met criteria for classification as NIFTP and, 17 (34%) were classified as encapsulated FVPTC with invasion. Strict application of architectural features led to classification of 12 (24%) tumors as non-FVPTC with a variety of more aggressive designations. Tumors classified as NIFTP and encapsulated FVPTC with invasion lacked lymph node metastases (0/4; 0/7, respectively) and BRAF mutations (0/12; 0/13, respectively). In contrast, infiltrative FVPTC, encapsulated PTC with or without invasion, and conventional PTC showed more aggressive features with lymph node metastases and BRAF V600E mutations. One case not meeting criteria for NIFTP maintained the diagnosis of encapsulated FVPTC without invasion but demonstrated significant mitotic activity (three mitoses/ten HPF) and lacked lymph node metastases and BRAF V600E mutation. These findings demonstrate the importance of using strict criteria, especially the lack of true papillary architecture, for the diagnosis of NIFTP and encapsulated FVPTC to ensure that only truly indolent tumors will be included in these diagnoses and to allow tumors with potential for more aggressive behavior to be appropriately treated. [ABSTRACT FROM AUTHOR]

The term noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed to replace noninvasive follicular variant of papillary thyroid carcinoma (FVPTC) both to promote more conservative management of these tumors and spare patients the psychological burden of a cancer diagnosis. This reclassification will lower the incidence of papillary thyroid carcinoma (PTC). In addition, it could result in an increase in the rates of unfavorable histologic prognosticators for PTC overall because NIFTPs had previously accounted for many of the PTCs without these features. Our aim was to evaluate the potential impact of the reclassification of NIFTP on the rates of extrathyroidal extension, lymphovascular invasion, and lymph node metastases in PTC. We identified all PTCs clinically over 1 cm diagnosed on surgical resection between August 2010 and August 2012. The histopathologic characteristics, including PTC subtype, tumor size, presence of extrathyroidal extension and lymphovascular invasion, and surgical margin and lymph node status were all recorded. Based on these parameters, cases were classified according to the American Thyroid Association (ATA) risk stratification system for structural disease recurrence. Tumor slides for cases initially diagnosed as FVPTC were reviewed to identify tumors that would now be classified as NIFTPs. Our cohort included 348 cases of PTC, of which 94 (27%) would now be classified as NIFTPs. After excluding NIFTPs from the PTC category, there were increased rates of extrathyroidal extension (26% up from 19%, p = 0.046), lymphovascular invasion (37% up from 27%, p = 0.0099), and lymph node metastases (26% up from 19%, p = 0.045) among the remaining PTCs. Based on these changes in histologic features, 10% fewer cases were defined as ATA low risk (62% down from 72%, p = 0.0081). Our results indicate that the downgrading of some carcinomas to NIFTP will increase the rates of higher risk histologic parameters in the remaining PTCs by statistically significant margins. Although the overall survival for PTC is very high and would likely not be changed significantly by the introduction of NIFTP, additional studies evaluating the impact of the NIFTP shift are warranted. [ABSTRACT FROM AUTHOR]

This study compared the expression profile of HBME-1 and claudin-1 in 90 papillary thyroid carcinomas (PTCs) with respect to the tumor architecture and invasive growth as reflected in 46 BRAF-like, 31 non-invasive RAS, and 13 invasive RAS-like phenotypes. Individual tumors were given an expression score (max 300) by multiplying the percent positive tumor cells by the intensity score (range 0-3). The higher expression of HBME-1 and claudin-1 distinguished BRAF-like phenotype from RAS-like phenotype. The same correlation was also retained for both markers when comparing BRAF-like phenotype with non-invasive and invasive RAS-like phenotypes. The expression scores and positivity rates for both markers did not yield any statistical difference among BRAF-like PTCs. Except the higher positivity rate of HBME-1, invasive RAS-like tumors were not statistically different than their non-invasive counterparts with respect to the positivity rate of claudin-1 and the expression scores of both markers. A central lymph node dissection or selective lymph node sampling was available in 20 specimens. The absence of claudin-1 expression has not been a feature of lymph node metastasis in this series. Despite the limited number of nodal sampling, BRAF-like phenotype and claudin-1 positivity status have been considered the best determinants of positive predictive value and negative predictive value in the prediction of lymph node metastasis among variables, respectively. Adoption of the simplified architectural classification approach to PTCs showed distinct biomarker expression profile in this series; however, immunohistochemistry for HBME-1 and claudin-1 does not seem to be useful in the distinction of invasive RAS-like PTCs from their non-invasive counterparts. Given the overlapping molecular signatures within the RAS-like phenotype, further studies with additional biomarkers are still needed to identify distinct protein expression signatures of non-invasive RAS-like phenotype as this diagnostic category still remains a surgical diagnosis at this time. [ABSTRACT FROM AUTHOR]