Encapsulated Follicular Variant Of Papillary Thyroid Carcinoma Research Articles

In silico annotation of follicular thyroid neoplasm associated metabolic pathways and involved biomarkers: An aid to diagnosis

The follicular thyroid neoplasm (FTN) is like an unsolved puzzle at some stage in preoperative diagnosis. Usually, for preliminary characterization of thyroid lesions, clinicians depend much on fine-needle aspiration cytology (FNAC). However, in the case of FTN, FNAC cannot distinguish between benign and malignant entities, as both are exhibiting predominant follicular architecture. Cytological/ architectural/ or cellular criteria alone is not enough to differentiate Follicular adenoma (FA), Follicular thyroid carcinoma (FTC), Follicular variant of papillary thyroid carcinoma (FVPTC) together with Non-Invasive Follicular variant of Papillary Thyroid Carcinoma (NIFTP), Encapsulated FVPTC (EFVPTC) and well-differentiated neoplasm of uncertain malignant potential. Thus, the genetic analysis can be used as a novel diagnostic approach that should be applied with the traditional method for easy diagnosis of follicular thyroid neoplasm, which reduces the risk of unnecessary surgeries. This present study tried to explore the current genetic assessment of FTN through review of the genetics of FTN studied from 2009 to 2019 which showed the characterization of differential gene expression in these follicular neoplasms some extent. Also, pathway analysis has potentially implemented to minimize the diagnosis dilemma. In addition to the previously identified pathways and associated target genes, some novel endocrine cancer-related pathways with putative target genes of FTN have been remoted from characterizing tumor with follicular pattern. The observed genes might be considered as diagnostic biomarker in the respective FTN associated metabolic pathways.

“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.

Molecular Profiles of Noninvasive, Minimally Invasive, and Invasive Follicular Patterned Thyroid Neoplasms with Papillary Nuclear Features.

Background: An increasing amount of data is being published, which risk-stratify thyroid tumors according to genetic signatures and histological morphology. Typically, follicular patterned lesions have been shown to harbor RAS-like mutations with more indolent behaviors. Our study aims to examine the extent of similarity among three groups of follicular patterned lesions with papillary nuclear features-noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) with capsular invasion and/or angioinvasion, and infiltrative follicular variant of papillary thyroid carcinoma (iFVPTC)-to help clarify whether NIFTP and EFVPTC represent a histological continuum and the degree to which the genomic landscape further separates higher risk follicular patterned tumors such as iFVPTC from more indolent ones (EFVPTC and NIFTP). Methods: ThyroSeq test results were compared for cases with histological NIFTP, EFVPTC, and iFVPTC in this retrospective study. Genetic drivers were subcategorized by level of aggressiveness. Gene expression alterations (GEAs) and copy number alterations (CNAs) were compared among the three histological groups. Results: NIFTP and EFVPTC cases displayed predominantly RAS-like alterations (100% and 75%, respectively) and RAS-like GEAs (55.2% and 47.2%, respectively), and many showed CNAs with 22q-loss. Despite a predominance of RAS-like alterations, EFVPTC cases showed molecular heterogeneity with significantly more intermediate and aggressive drivers (22.3% of cases) than NIFTP (0%) (p = 0.0068). iFVPTC cases displayed molecular profiles in between that of traditional follicular patterned lesions and classical papillary thyroid carcinoma, predominantly displaying intermediate and aggressive drivers (61.6%), which was significantly higher than that of EFVPTC (22.3%, p = 0.0158) and NIFTP (0%, p < 0.0001), illustrating the higher MAP kinase activity of iFVPTC. There was no significant difference, however, in comparing GEAs among the three histological groups. Conclusions: While follicular patterned lesions with papillary nuclear features overall tend to display RAS-like alterations, EFVPTC cases, followed by iFVPTC in this series, showed increasing proportions of more aggressive drivers. EFVPTC and NIFTP show much molecular overlap, with predominance of RAS-like alterations, suggesting that these tumors are part of a genetic continuum, while still ranked differentially. Preoperative molecular testing can potentially distinguish EFVPTC and iFVTPC from NIFTP based on a particular molecular signature, optimizing patient management.

Sonographic and clinicopathological differences between non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and minimally invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

An unexpected cervical unicentric Castleman disease disguising as a lymph node metastasis of papillary thyroid carcinoma

The onset of cervical lymph nodes could be a turning point in the oncologic management of patients previously treated for differentiated thyroid cancer. Its accurate diagnosis may be challenging. A 56-year-old female patient was diagnosed with papillary thyroid carcinoma (PTC). The initial surgical procedure included total thyroidectomy and prophylactic bilateral central-compartment neck dissection. The pathologic examination featured a 3-centimeter left-sided encapsulated follicular variant of PTC, without vascular invasion nor lymph nodes (LN) metastases. The tumor was staged pT2N0M0 and considered as ATA low risk. We obtained a radioiodine remnant ablation following a cumulative dose of 100 mCi. The response to therapy was excellent: indetectable stimulated thyroglobulin (TgOFF), negative anti-thyroglobulin auto-antibodies (TgAB), and negative imaging. After a 10-year remission, follow-up neck ultrasonography detected solid left-sided lymphadenopathy of level III measuring 86 × 31 mm with slightly concomitant rising TgOFF and positive TgAB, suggesting a possible PTC LN metastasis. The patient underwent surgical resection with favorable outcomes. The recurrence of PTC in the absence of aggressive histological features is unlikely (< 5% of cases). The onset of enlarged cervical lymphadenopathy with biochemical signs of cancer activity in patients with underlying PTC suggests a disease relapse. The pathologic examination revealed a unicentric plasmacytic variant of Castleman disease (UCD), with no evidence of malignancy. Castleman disease (CD) represents a cluster of rare and heterogeneous disorders with distinctive LN histopathological abnormalities. CD can occur in a single LN station [unicentric CD] or involve multiple LN stations with systemic symptoms [multicentric CD]. Mediastinum (29%) and abdominal (21%) sites are the most commonly implicated. Since cervical UCD can potentially mimic PTC lymph metastasis, the distinction between these two conditions is challenging. Only biopsy and histological proof could establish a conclusive diagnosis, allowing appropriate management for each scenario.

Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features: What a Surgeon Should Know.

The inclusion of the less aggressive follicular form of papillary thyroid cancer (PTC) is associated with an increase in the incidence of the condition, with the follicular variant of PTC being the most common of all variants. The majority of individuals with the encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) are treated as though they have classic thyroid cancer, despite the availability of mounting evidence to contradict the aforementioned. According to numerous research, a certain type of noninvasive-EFVPTC (NI-EFVPTC) demonstrated poor histopathologic diagnostic reproducibility and has received aggressive treatment similar to that of a classical thyroid neoplasm. Therefore, to replace the term NI-EFVPC, a new nomenclature for these tumors, called "noninvasive follicular thyroid neoplasm with papillary-like nuclear characteristics" (NIFTP), was introduced in the year 2016. The present paper explores this recently introduced terminology, clinical, histologic, and molecular features, and diagnostic criteria.

Clinicopathologic Characteristics of Pediatric Follicular Variant of Papillary Thyroid Carcinoma Subtypes: A Retrospective Cohort Study.

Introduction: Follicular patterned thyroid nodules with nuclear features of papillary thyroid carcinoma (PTC) encompass a range of diagnostic categories with varying risks of metastatic behavior. Subtypes include the invasive encapsulated follicular variant of PTC (Ienc-fvPTC) and infiltrative fvPTC (inf-fvPTC), with tumors lacking invasive features classified as noninvasive follicular thyroid neoplasms with papillary-like features (NIFTPs). This study aimed to report the clinical and histological features of pediatric cases meeting criteria for these histological subtypes, with specific focus on Ienc-fvPTC and inf-fvPTC. Methods: In this retrospective cohort study, pediatric patients with thyroid neoplasms showing follicular patterned growth and nuclear features of PTC noted on surgical pathology between January 2010 and January 2021 were retrospectively reviewed and classified according to the recent 2022 World Health Organization (WHO) criteria. Clinical and histopathologic parameters were described for NIFTP, Ienc-fvPTC, and inf-fvPTC subtypes, with specific comparison of Ienc-fvPTC and inf-fvPTC cases. Results: The case cohort included 42 pediatric patients, with 6 (14%), 25 (60%), and 11 (26%) patients meeting criteria for NIFTP, Ienc-fvPTC, and inf-fvPTC, respectively. All cases were rereviewed, and 5 patients originally diagnosed with Ienc-fvPTC before 2017 were reappraised as having NIFTPs. The NIFTP cases were encapsulated tumors without invasive features, lymph node or distant metastasis, or disease recurrence. Ienc-fvPTC tumors demonstrated clearly demarcated tumor capsules and capsular/vascular invasion, while inf-fvPTC tumors displayed infiltrative growth lacking a capsule. inf-fvPTC cases had increased prevalence of malignant preoperative cytology, lymph node metastasis, and distant metastasis (p < 0.01). These cases were treated with total thyroidectomy, lymph node dissection, and subsequent radioactive iodine therapy. Preliminary genetic findings suggest a predominance of fusions in inf-fvPTC cases versus point mutations in Ienc-fvPTC (p = 0.02). Conclusions: Pediatric NIFTP and fvPTC subtypes appear to demonstrate alignment between clinical and histological risk stratification, with indolent behavior in Ienc-fvPTC and invasive features in inf-fvPTC tumors.

Lésions thyroïdiennes folliculaires encapsulées, classifications histologique et pTNM, examen extemporané et évaluation histopathologique

AbstractEncapsulated follicular-patterned thyroid tumors remain the daily challenge for pathologists, including experts. The differential diagnosis typically includes hyperplastic/adenomatous nodule, follicular adenoma, follicular carcinoma, follicular variant of papillary thyroid carcinoma (FVPTC), and non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The latter is a new terminology that was integrated into the WHO 2017 classification of endocrine tumors to replace the majority of non-invasive encapsulated FVPTC. Capsular and/or vascular invasion remains the main sign of malignancy. This invasion is, in the majority of cases, microscopic and necessitating an examination of the entire capsule. And for this reason, the frozen section is most often useless. The risk of recurrence and mortality correlates more with the importance of vascular invasion than with the size of the tumor and the management of these lesions must be discussed on a case-by-case basis and should not depend solely on the pTNM stage.

Diagnostic Value of Galectin-3 in Distinguishing Invasive Encapsulated Carcinoma from Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features (NIFTP).

Simple SummaryThe reclassification of NIFTP raised the need for rebuilding the clinical, histologic, cytological and molecular parameters, including re-evaluation of the previously examined biomarkers, for assisting in the diagnosis of this subset of indolent noninvasive tumors from invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). In this retrospective study, Galectin-3 (Gal-3) IHC staining on patient’s thyroid tissues showed a statistically significant higher cytoplasmic Gal-3 expression in invasive EFVPTC than in NIFTP and other benign subgroups. Our findings refined the diagnostic value of Gal-3 expression as an ancillary marker in identifying NIFTP among encapsulated follicular variant nodules.Background: non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), which is considered as low-risk cancer, should be distinguished from the malignant invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). Improved discrimination of NIFTPs from invasive EFVPTCs using a molecular biomarker test could provide useful insights into pre- and post-surgical management of the indeterminate thyroid nodule. Galectin-3 (Gal-3), a β-galactosyl-binding molecule in the lectin group, is involved in different biological functions in well differentiated thyroid carcinomas. The aim of this study was to determine whether Gal-3 expression as a diagnostic marker could distinguish indolent NIFTP from invasive EFVPTC on tissue specimens from surgical thyroid nodules. Methods: immunohistochemical (IHC) analysis of cytoplasmic and nuclear Gal-3 expression was performed in formalin-fixed paraffin-embedded (FFPE) surgical tissues in four specific diagnostic subgroups- benign nodules, NIFTPs, EFVPTCs and lymphocytic/Hashimoto’s thyroiditis (LTs). Results: cytoplasmic Gal-3 expression (mean ± SD) was significantly increased in invasive EFVPTCs (4.80 ± 1.60) compared to NIFTPs (2.75 ± 1.58, p < 0.001) and benign neoplasms (2.09 ± 1.19, p < 0.001) with no significant difference between NIFTPs and benign lesions (p = 0.064). The presence of LT enhanced cytoplasmic Gal-3 expression (3.80 ± 1.32) compared to NIFTPs (p = 0.016) and benign nodules (p < 0.001). Nuclear Gal-3 expression in invasive EFVPTCs (1.84 ± 1.30) was significantly higher than in NIFTPs (1.00 ± 0.72, p = 0.001), but similar to benign nodules (1.44 ± 1.77, p = 0.215), thereby obviating its potential clinical application. Conclusions: our observations have indicated that increased cytoplasmic Gal-3 expression shows diagnostic potential in distinguishing NIFTP among encapsulated follicular variant nodules thereby serving as a possible ancillary test to H&E histopathological diagnostic criteria when LT interference is absent, to assist in the detection of the invasive EFVPTC among such nodules.

Are molecular tests necessary to diagnose NIFTP?

In 2016, encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). In 2018 the criteria for NIFTP were widened by the inclusion of the complete lack of papillae. Secondary criteria, which include molecular examination, are helpful but not required for NIFTP diagnose.The aim of this study was to assess the molecular background of NIFTP and to answer the question if the aplication of revised criteria for NIFTP diagnosis is associated with the lack of oncogenic mutation.Repeat histopathological assessment of 1117 cases of papillary thyroid carcinoma (PTC) from 2000-2016 was conducted. Using initial (2016) and revised (2018) diagnostic criteria, NIFTP was diagnosed in 23 and 13 patients respectively. 50 tumor genes hotspots mutation analysis was conducted. BRAFV600E mutations were detected in patients who fulfilled only initial NIFTP criteria. Other high-risk mutations (TP53) were found in both groups of patients.The application of restrictive, revised diagnostic criteria for NIFTP negates the need for BRAFV600E examination, but these tumors still can harbor other high-risk oncogenic mutations nonetheless. Thus, molecular examination should be considered as a necessary step in NIFTP diagnostic process.

Clinicopathological parameters for predicting non-invasive follicular thyroid neoplasm with papillary features (NIFTP).

Background:Criteria for the preoperative diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) have not yet been confirmed. This study aimed to analyze differences in clinicopathological characteristics between follicular variant of papillary thyroid carcinoma (FVPTC) subtypes to determine which parameters are relevant in differentiating NIFTP from other variants.Methods:We retrospectively analyzed the records of 199 patients with a preoperative diagnosis of FVPTC who underwent thyroid surgery at Seoul St. Mary’s Hospital (Seoul, Korea) from 2011 to 2015. Clinicopathological features were analyzed retrospectively via a complete review of medical charts and pathology reports of patients.Results:The NIFTP and invasive encapsulated FVPTC (EFVPTC) groups showed relatively benign features, with a majority of the patients categorized as Bethesda category III (25.8% and 25.6%, respectively) or IV (34.8% and 30.2%, respectively), while the infiltrative FVPTC group showed more malignant features, with more patients categorized as category V (28.6%) or VI (47.6%) (p < 0.001). BRAFV600E mutations were significantly less prevalent in the NIFTP group (0%) and invasive EFVPTC group (4.7%) compared with the infiltrative FVPTC group (34.9%) (p < 0.001). Multivariate analysis showed that absence of BRAFV600E mutation (OR 20.311, p = 0.004) and lymph node metastasis (odds ratio 10.237, p = 0.004) were significantly associated with NIFTP.Conclusion:Although Bethesda category was a statistically significant factor in distinguishing FVPTC subtypes, it was not effective in conclusively distinguishing NIFTP and invasive EFVPTC. Absence of BRAFV600E mutation and lymph node metastasis are important features in distinguishing NIFTP from other subtypes.

Influence of Nomenclature Changes on Trends in Papillary Thyroid Cancer Incidence in the United States, 2000 to 2017.

US papillary thyroid carcinoma (PTC) incidence recently declined for the first time in decades, for reasons that remain unclear. This work aims to evaluate PTC incidence trends, including by histologic subtype and size, and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This descriptive study uses US Surveillance, Epidemiology, and End Results-18 cancer registry data (2000-2017). Participants included individuals diagnosed with PTC (2000-2017) or NIFTP (2016-2017). During 2000 to 2015, PTC incidence increased an average 7.3% per year, (95% CI, 6.9% to 7.8%) during 2000 to 2009, and 3.7% per year (95% CI, 0.2% to 7.3%) during 2009 to 2012, before stabilizing in 2012 to 2015 (annual percentage change [APC] = 1.4% per year, 95% CI, -1.8% to 4.7%) and declining in 2015 to 2017 (APC = -4.6% per year, 95% CI, -7.6% to -1.4%). The recent declines were observed for all sizes of PTC at diagnosis. Incidence of follicular variant of PTC (FVPTC) sharply declined in 2015 to 2017, overall (APC = -21.1% per year; 95% CI, -26.5% to -15.2%) and for all tumor sizes. Observed increases in encapsulated papillary carcinoma (classical PTC subtype) and NIFTP each accounted for 10% of the decline in FVPTC. Classical PTC incidence continuously increased (2000-2009, APC = 8.7% per year, 95% CI, 8.1% to 9.4%; 2009-2017, APC = 1.0% per year, 95% CI, 0.4% to 1.5%), overall and for all sizes except smaller than 1 cm, as did incidence of other PTC variants combined (2000-2017, APC = 5.9% per year, 95% CI, 4.0% to 7.9%). The reasons underlying PTC incidence trends were multifactorial. Sharp declines in FVPTC incidence during 2015 to 2017 coincided with clinical practice and diagnostic coding changes, including reclassification of noninvasive encapsulated FVPTC from a malignant to in situ neoplasm (NIFTP). Observed increases in NIFTP accounted for 10% of the decline in FVPTC.

MON-434 Encapsulated Follicular-Variant of Micropapillary Carcinoma Presenting with Distant Bony Metastasis

INTRODUCTION The incidence of thyroid cancer has risen steadily over the last decades, in part due to increasing diagnosis of apparently low-risk well-differentiated cancers. The outcomes of well-differentiated thyroid cancers, including follicular variant papillary thyroid carcinoma (PTC), are believed to be quite favorable, with a largely indolent benign course. We examine an encapsulated follicular-variant of micropapillary carcinoma presenting with distant bony metastasis. CASE 55-year-old lady presented to clinic after biopsy of iliac crest (IC) mass revealed thyroid tissue. One year prior she started having dull pain at right hip, attributed to increased physical activity. She noticed a tender “lump” on her right hip. CT revealed destructive right iliac 8 cm mass with extraosseous soft tissue component, central necrosis, and eccentric calcifications; and right ovarian cyst. Right IC biopsy was consistent with thyroid tissue with positive Thyroglobulin and TTF-1 immunostains. Physical exam was normal, except for mild tachycardia, hypertension, right flank large rounded mass fixed to IC, tender to palpation without erythema or warmth on overlying skin. Thyroid ultrasound showed normal thyroid gland except 5.58 x 6.22 x 7.76 mm left lobe nodule without increased vascularity but with coarse peripheral calcification. FNA was unsatisfactory. Thyroid function tests revealed undetectable TSH, elevated FT4, FT3, and markedly elevated thyroglobulin and TSI. PET/CT scan showed focal area of mild FDG avidity, corresponding to the right iliac crest mass, without additional areas of FDG avidity suggestive of metastatic disease or primary neoplastic process. Three weeks after presentation, patient began having symptoms of hyperthyroidism. As FT4 and FT3 continued to rise, she was started on propranolol and methimazole. Due to inadequate response, methimazole was switched to high dose propylthiouracil with mild improvement. Thyroid uptake and scan and SPECT-CT revealed increased thyroid uptake and thyromegaly consistent with Graves’ disease and redemonstrated large right IC lesion with increased uptake in the periphery and central photopenia, suggesting metastatic thyroid malignancy. Pathology from total thyroidectomy reported encapsulated follicular variant of PTC, confined to the left lobe of the thyroid, without extrathyroidal extension, greatest tumor dimension 0.6cm. As metastasis to the IC were unlikely to have originated from this small encapsulated thyroid cancer, it was recommended to proceed with right oophorectomy for suspected malignant struma ovarii and IC lesion debulking. Surgical pathology revealed right ovary and fallopian tube without pathologic changes or features of teratoma and tissue from right iliac mass consistent with PTC. Patient is off all antithyroid medications and remains biochemically euthyroid, awaiting radioactive iodine therapy.

Long-term progression of non-invasive follicular thyroid neoplasm with papillary-like nuclear features: A single-center retrospective study of the French Marne–Ardennes thyroid cancer registry

ContextNon-invasive forms of encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) were reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in order to reduce overtreatment. A few studies showed neck lymphadenopathy at diagnosis, or even distant metastasis in patients with NIFTP. ObjectiveOur aim was to report the frequency, clinical features and long-term progression of histologically confirmed NIFTP, using data from the French Marne–Ardennes thyroid cancer registry, and to compare findings against FVPTC. MethodsThis was a retrospective study on data for follicular variant of PTC (FVPTC) diagnosed between 1975 and 2015 obtained from the specialized Marne–Ardennes thyroid cancer registry. Pathology reports were used to select appropriate cases from a large series, and FVPTC specimens were reviewed by endocrine pathologists. Strict diagnostic criteria were used for reclassification as NIFTP. ResultsIn total, 115 cases were reviewed histologically out of 383 cases of FVPTC. Sixty-five met all criteria for NIFTP and were consequently reclassified. Incidence of NIFTP was 16.9% of cases of FVPTC. Fifty patients were women (76.9%); median age was 47 years. Mean NIFTP size was 2.6 cm. There were no significant differences in age, gender or tumor size between NIFTP and FVPTC. Fifty patients underwent total thyroidectomy and 15 lobectomy. There were no lymph node metastases at diagnosis, and none of the patients (N=17) who underwent central and/or lateral neck dissection had positive findings on microscopic examination. 46 patients (70.8%) received radioiodine (RAI). Patients were followed up for 1.9–27.3 years (median 14.6 years) after initial treatment. All patients remained in complete remission during follow-up. ConclusionConsistently with previous studies, our results showed the indolent course of NIFTP and that risk of recurrence after complete resection is very low (zero in our cohort), even when size is ≥4cm and in absence of adjuvant RAI treatment. Prospective studies are needed to confirm those results.

Diagnostic significance of apical membranous and cytoplasmic dot-like CD26 expression in encapsulated follicular variant of papillary thyroid carcinoma: a useful marker for capsular invasion.

Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and invasive encapsulated follicular variant of papillary thyroid carcinoma (EFV-PTC) are indistinguishable preoperatively. CD26 expression in follicular tumor-uncertain malignant potential (FT-UMP) is reported to be clearly higher than in that without capsular invasion. To verify the diagnostic significance of CD26 immunostaining in EFV-PTC, we examined the expression pattern of CD26 in non-invasive EFV-PTC (NIFTP) and invasive EFV-PTC. We performed immunohistochemical analysis using CD26 antibody for 37 NIFTPs and 54 EFV-PTCs (34 minimally invasive EFV-PTCs and 20 widely invasive EFV-PTCs). Most NIFTP samples showed an apical membranous pattern or a cytoplasmic diffuse pattern of expression. Invasive EFV-PTCs more frequently showed a cytoplasmic dot-like pattern, and the labeling indices of tumor cells with cytoplasmic dot-like patterns were significantly higher than those in NIFTPs. The sizes of dots seen in NIFTPs (mean: 1.12 μm) were significantly smaller than in invasive EFV-PTCs (1.33 μm), minimally invasive EFV-PTC (1.27 μm), and widely invasive EFV-PTC (1.38 μm). We, therefore, conclude that cytoplasmic diffuse and/or cytoplasmic dot-like CD26 expression, particularly the larger CD26-positive dots, could be useful markers for capsular invasion in EFV-PTC. CD26 immunostaining, using cell blocks or cytological specimens, may preoperatively distinguish between NIFTP and invasive EFV-PTC.

Preoperative Diagnostic Categories of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features in Thyroid Core Needle Biopsy and Its Impact on Risk of Malignancy.

This study was designed to evaluate the preoperative diagnostic categories of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) using thyroid core needle biopsy (CNB) and to analyze its impact on the risk of malignancy (ROM). A total of 2687 consecutive thyroid CNBs were reviewed retrospectively and classified into six diagnostic categories using a standardized reporting system similar to the Bethesda System for Reporting Thyroid Cytopathology. Diagnostic categories of CNBs were compared with the final surgical diagnoses, and the ROM in each category was calculated both before and after excluding NIFTP from malignancy. Of 946 surgically resected cases, 683 were diagnosed as papillary thyroid carcinoma (PTC), and 32 (4.7% of PTC) were reclassified as NIFTP. The CNB diagnostic categories of NIFTP were as follows: follicular neoplasm in 20 (62.5%; 14, with nuclear atypia), indeterminate lesion in 11 (34.4%), and suspicious for malignancy in one (3.1%). When combined, NIFTP and encapsulated follicular variant of PTC (EFVPTC) were more often categorized as follicular neoplasm compared with other PTC variants including infiltrative FVPTC. Exclusion of NIFTP from malignant diagnosis led to a significant decrease in the ROM in follicular neoplasm with nuclear atypia category. Thus, thyroid CNB enables to differentiate NIFTP/EFVPTC from other PTCs, providing a useful guide for optimal treatment in patients with these tumors.

How Does Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features (NIFTP) Compare to Encapsulated and Nonencapsulated Follicular Variants of Papillary Thyroid Carcinoma? An Examination Into Next-Generation Sequencing Molecular Profiles

Abstract Objectives With the removal of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) from the follicular variant of papillary thyroid carcinoma (FVPTC) categorization, the question arises as to how the molecular profile of invasive encapsulated FVPTC (IEFVPTC) compares with NIFTP. Our study aimed to examine the molecular alterations associated with NIFTP, IEFVPTC, and infiltrative FVPTC (iFVPTC) to determine whether these entities are actually distinct at the molecular level. Methods Forty-five NIFTP cases, 12 IEFVPTC cases, and 8 iFVPTC cases from 1/2013 to 8/2016 were assessed for presurgical fine-needle aspiration ThyroSeq V2 next-generation sequencing results. Results The NIFTP cases displayed alterations in BRAF K601E/EIF1AX, BRAF T599_R603, NRAS x15 (two with additional PTEN and one with P53), KRAS x3, HRAS x11 (one with an additional TERT/EIF1AX), PAX8-PPARgamma x5, PTEN, THADA x3, MET x2, copy number alteration, EF1AX, and DICER1. The IEFVPTC displayed alterations in RAS x5 (1 NRAS/TERT, 2 HRAS, 2 NRAS), BRAF-K601E x2, and BRAF-pG469A with gene expression profile; PAX8-PPARgamma x2; THADA-IGF2BP3; and ETV6/NTRK3. The iFVPTC cases displayed alterations in RAS x2 (NRAS and HRAS), TERT x2, BRAF-V600E mutation, ALK, MET, and NTRK3. Conclusion NIFTP and IEFVPTC cases most commonly displayed RAS mutations (64.4% and 41.7%, respectively) and lacked aggressive BRAF-V600E mutations, whereas iFVPTC harbored aggressive mutations such as BRAF-V600E and TERT more commonly, with fewer RAS mutations. The possibility of NIFTP and IEFVPTC being on a premalignant to malignant continuum must be raised and these entities may be more similar to each other than to other entities such as iFVPTC.

Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features in Children: An Institutional Experience and Literature Review.

Papillary thyroid carcinoma (PTC) in children has a distinctive set of clinicopathologic features and molecular signature compared to their adult counterparts. The recent recommendation to reclassify encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) without invasion as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is based on evidence derived almost exclusively from studies in adults. Clinicopathologic studies restricted to pediatric NIFTP are limited. We retrospectively analyzed all pediatric PTC and NIFTP diagnosed and treated in our institution from 1999 to 2016 (n = 31). Using recently published consensus diagnostic criteria, we identified 3 NIFTP and 2 infiltrative follicular variants of papillary thyroid carcinoma (FVPTC) among 31 cases. Two of the NIFTP cases were initially diagnosed as EFVPTC. All 3 patients with NIFTP had unifocal tumors of lower American Joint Committee on Cancer (AJCC) classification (T2 or lower) and were free of lymph node or distant metastasis. Total (n = 1) or completion (n = 2) thyroidectomy was performed in all cases, and only 1 NIFTP patient received subsequent radioablative therapy. No residual or recurrent disease has been observed during follow-up (15-138 months) in patients with NIFTP. Our experience with NIFTP in children is similar to outcomes reported in adult studies, suggesting that pediatric NIFTP behave indolently as evidenced by the absence of local recurrence in our cohort.

Utility of Tumor Capsule Thickness as a Predictor of Invasion in Encapsulated Follicular Variant of Papillary Thyroid Carcinoma and a Diagnostic Tool for Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features.

Context. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is an extremely indolent subset of noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC). These lesions share certain features including a delimiting fibrous capsule, and they are distinguished by detailed histological criteria. Objective. We sought to identify whether tumor capsule thickness differs significantly between NIFTP and noninvasive EFVPTC lesions. We also compared tumor capsule thickness between noninvasive and invasive EFVPTC in order to evaluate its utility as a predictive marker of invasion. Design. Encapsulated follicular thyroid neoplasms with papillary-like nuclear features diagnosed over a 3-year period at a single institution were subcategorized into NIFTP, noninvasive EFVPTC, and invasive EFVPTC based on current diagnostic criteria. Maximum tumor capsule thickness for each lesion was measured. Results. A total of 92 lesions (39 NIFTP, 15 noninvasive EFVPTC, and 38 invasive EFVPTC) were evaluated. Tumor capsule thickness was significantly thinner in NIFTP (P = .022) and significantly thicker in invasive EFVPTC (P = .0006) when compared with noninvasive EFVPTC. Conclusions. Tumor capsule thickness may be an additional useful marker when distinguishing between NIFTP and noninvasive EFVPTC. A capsule thickness of greater than 0.2 mm should raise suspicion for EFVPTC and thus prompt more thorough review of the submitted tissue for NIFTP exclusionary criteria. Additionally, if capsular and/or vascular invasion are not present on initial slides of an entirely evaluated capsule of EFVPTC that exceeds 0.5 mm in thickness, the pathologist should order additional tissue levels to ensure that a small focus of invasion is not missed.

Risk of Malignancy in Thyroid Cytology: The Impact of The Reclassification of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP)

Objective: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We aimed to compare the risk of malignancy (ROM) of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) on fine-needle aspiration cytology (FNAC), before and after the reclassification, in a large cohort of patients. Methods: We analyzed 5,625 consecutive FNAC samples performed in 2012-2014 and selected category III (atypia of undetermined significance [AUS]/follicular lesion of undetermined significance [FLUS]), IV (follicular neoplasm [FN]/suspicious for a follicular neoplasm [SFN]), V (suspicious for malignancy [SFM]), and VI (malignant) of the BSRTC. We reviewed the histology of operated patients and compared ROM before and after the introduction of the NIFTP category. Results: A total of 772 patients were identified and 45% underwent surgery (n = 348). There were 180 cases of AUS/FLUS (10 NIFTP), 114 cases of FN/SFN (2 NIFTP), 29 cases of SFM (3 NIFTP), and 25 cases of BSRTC VI (no NIFTP). Exclusion of NIFTP from malignant lesions resulted in a relative and absolute decrease in the ROM in AUS/FLUS (15.2% and 5.5%, respectively), FN/SFN (7.6% and 1.8%, respectively) and SFM (14.2% and 10.3%, respectively) categories. Among the NIFTP patients, 93% underwent total thyroidectomy and 20% received radioiodine. Conclusion: Reclassification of noninvasive EFVPTC as NIFTP resulted in a decrease in overall ROM, and the BSRTC categories most affected were III and V. Abbreviations: AUS = atypia of undetermined significance; BSRTC = Bethesda System for Reporting Thyroid Cytopathology; EFVPTC = encapsulated follicular variant of papillary thyroid carcinoma; FLUS = follicular lesion of undetermined significance; FN = follicular neoplasm; FNAC = fine-needle aspiration cytology; FVPTC = follicular variant of papillary thyroid carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PTC = papillary thyroid carcinoma; ROM = risk of malignancy; SFM = suspicious for malignancy; SFN = suspicious for a follicular neoplasm.