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

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

Oncocytic/Hürthle cell lesions have the same implied risk of neoplasm/malignancy as their follicular counterparts.

INTRODUCTION: There are conflicting results on whether the presence of oncocytes modifies the risk of neoplasm (RON) or malignancy (ROM) for thyroid fine-needle aspirates (FNAs): Atypia of undetermined significance AUS and Follicular Neoplasm, FN, or Oncocytic Neoplasm, ON. To our knowledge, the effect of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has not yet been studied. We compared RON and ROM between follicular type AUS (AUS-FT) and oncocytic type AUS (AUS-OT) and between FN and ON. MATERIALS AND METHODS: We retrospectively analysed all thyroid FNAs with the diagnostic category of AUS-other or Neoplasm (2005-2015). AUS-FT had predominance of microfollicles and AUS-OT had predominance of oncocytes. Histology follow-up was then reviewed and RON, ROM was then calculated and compared (significant at p < 0.05). We repeated the search for 2018 to evaluate for NIFTP effect. RESULTS: Pre-NIFTP, 859/5063 cases (17%) were AUS-FT, AUS-OT, FN, and ON. Histology follow-up was available for 297 cases (35%). RON was 83/183 (45%) for AUS-FT, 35/76 (46%) for AUS-OT, 15/25 (60%) for FN and 11/13 (85%) for ON. Post-NIFTP, RON was 11/31 (35%) for AUS-FT, 5/8 (63%) for AUS-OT, 1/2 (50%) for FN and 4/5 (80%) for ON. For both periods, RON, ROM of AUS-FT was not significantly different than AUS-OT, and no significant differences were observed comparing FN and ON. CONCLUSION: The predominance of oncocytes does not modify the implied RON, ROM for categories of AUS or FN\ON, even after the adoption of NIFTP.

Evaluation of the follicular patterned thyroid lesions based on the WHO 2022 criteria with an emphasis on the grey-zone lesions.

Follicular-patterned thyroid nodules (FPTN) are classified byWHO-2022 into benign, borderline and malignant categories. There are however, grey-zone lesions that pose a diagnostic challenge due to ambiguity in defining criteria and inter-observer variability. WHO-2022 has enumerated specific diagnostic criteria for these lesions. Accurate categorization of morphologically similar TNs is vital to reduce overtreatment of indolent lesions. In this study, we have reclassified FPTNs according to WHO-2022 criteria, emphasizing on grey-zone lesions. We studied the utility of immunohistochemistry (IHC)-CD56, HBME-1 and CK19 in distinguishing benign from malignant nodules and BRAFV600E IHC to better distinguish the (widely-invasive) encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) from infiltrative FVPTC. Only those cases with dominant nodule having follicular pattern histology were included and re-evaluated for following histopathological features-focality, encapsulation, circumscription, nuclear PTC features, capsular-invasion, angio-invasion, papillae and necrosis. IHC findings for above-mentioned markers were noted. Seventy-nine cases met the inclusion criteria. Amendment of original diagnosis was done in 19 % cases. BRAFV600E IHC was positive in the two cases of infiltrative FVPTC while it was negative in all nine IE (invasive encapsulated) FVPTCs. Diffuse HBME1 was noted in most malignant nodules (61 %) while CD56 was expressed more often in benign lesions (70 %). CK19 was positive in lesions displaying nuclear PTC features (86 %). Using WHO 2022 criteria, we were able to re-classify follicular thyroid lesions with greater confidence. Appropriate IHC panel in adjunct to histology aids in categorizing challenging cases.

Spatially Resolved Molecular Approaches for the Characterisation of Non-Invasive Follicular Tumours with Papillary-like Features (NIFTPs).

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are low-risk thyroid lesions most often characterised by RAS-type mutations. The histological diagnosis may be challenging, and even immunohistochemistry and molecular approaches have not yet provided conclusive solutions. This study characterises a set of NIFTPs by Matrix-Assisted Laser Desorption/Ionisation (MALDI)-Mass Spectrometry Imaging (MSI) to highlight the proteomic signatures capable of overcoming histological challenges. Archived formalin-fixed paraffin-embedded samples from 10 NIFTPs (n = 6 RAS-mutated and n = 4 RAS-wild type) were trypsin-digested and analysed by MALDI-MSI, comparing their profiles to normal tissue and synchronous benign nodules. This allowed the definition of a four-peptide signature able to distinguish RAS-mutant from wild-type cases, the latter showing proteomic similarities to hyperplastic nodules. Moreover, among the differentially expressed signals, Peptidylprolyl Isomerase A (PPIA, 1505.8 m/z), which has already demonstrated a role in the development of cancer, was found overexpressed in NIFTP RAS-mutated nodules compared to wild-type lesions. These results underlined that high-throughput proteomic approaches may add a further level of biological comprehension for NIFTPs. In the future, thanks to the powerful single-cell detail achieved by new instruments, the complementary NGS-MALDI imaging sequence might be the correct methodological approach to confirm that the current NIFTP definition encompasses heterogeneous lesions that must be further characterised.

Intratumoural metastasis of primary lung adenocarcinoma to non-invasive follicular thyroid neoplasm with papillary-like nuclear features.

Metastasis to the thyroid gland is very uncommon with an incidence of 2-3% of all thyroid malignancies. A higher incidence is noted in autopsy studies indicating incidental detection. However, tumour-to-tumour metastasis is extremely uncommon with a handful of cases published in the literature to date. Also, non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFT-P) is a rare neoplasm; diagnosis requires meticulous sampling of the entire capsule and fulfilment of other diagnostic criteria. We report a case of primary adenocarcinoma of lung in a 57-year-old female who additionally had a left thyroid nodule which appeared suspicious on ultrasonography. Histology of lung tumour was conventional papillary adenocarcinoma while aspiration cytology from the thyroid raised suspicion of metastatic adenocarcinoma. On hemithyroidectomy, the thyroid nodule showed metastatic adenocarcinoma in the centre of the nodule, while the peripheral portion showed non-invasive follicular thyroid neoplasm with papillary-like nuclear features; the diagnosis of which was confirmed with complete sampling of the thyroid capsule. The immunoprofile also supported the above dual histology. This is an extremely uncommon occurrence and metastasis within a NIFT-P has not been reported to the best of our knowledge.

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.

TROP-2 and 5hmC expression in follicular-patterned thyroid neoplasm emphasizing tiny well-formed papillae.

BACKGROUND: Follicular-patterned thyroid neoplasms (FPTNs), characterized by predominantly follicular growth pattern, represent diverse pathological entities. We aimed to study the nuclear features and the immunoexpression of trophoblast cell-surface antigen 2 (TROP-2) and 5-hydroxymethylcytosine (5hmC) in FPTNs. DESIGN: FPTNs were divided into 4 groups: I) noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), II) encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) with capsular invasion, III) infiltrative FVPTC, and IV) PTC with a predominantly follicular pattern and well-formed papillae (<1%). Nuclear characteristics were evaluated by image analysis. TROP-2 and 5hmC immunostains were analyzed correlating with histological features using QuPath. RESULTS: From the group I to II, III, and IV, there is a gradual increase in nuclear atypia in terms of the nuclear area, max caliper, perimeter, circularity, and hematoxylin OD means (corresponding to nuclear enlargement, membrane irregularity, and clearing). A similar trend is observed in the TROP-2 expression. 5hmC expression is highly preserved in groups I, II, and III in contrast to a significant loss in group IV. Group IV tumors show more frequent regional lymph node involvement and the highest BRAF V600E mutation rate. CONCLUSION: Among FPTNs, group IV tumors exhibit the most advanced nuclear atypia, highest TROP-2 expression, significant 5HMC expression loss, frequent regional lymph node involvement, and the highest BRAF V600E mutation rate. Our data further support that the presence of any true papillae should be an exclusion criterion for NIFTP. Therefore, well-formed papillae even if very minute (<1% of the tumor) should not be overlooked.

Bone metastasis from noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP); a case report.

BACKGROUND: The term non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) was recently proposed as a non-malignant thyroid lesion with indolent behavior that does not require post-operative radio-iodine treatment. We are reporting a case of NIFTP with bone metastasis that is the second case reported so far. CASE PRESENTATION: We describe a 38-year-old woman who presented with an indeterminate thyroid nodule and underwent total thyroidectomy with the finding of NIFTP on careful pathologic examination. However, her initial follow-up evaluation revealed a serum thyroglobulin level of > 300 ng/ml and a diagnostic whole body 131I scan demonstrated a focus of increased uptake in the left hemipelvis, confirmed on CT scan to be a lytic lesion in the left iliac bone. She was treated with 7.4GBq (200 mCi) of 131I and her follow-up 1 year later revealed an undetectable serum thyroglobulin and a negative whole body 131I scan with no visible uptake in the iliac bone indicating an excellent response. CONCLUSION: This case presentation reminds us to be alert to the rare occurrence of distant metastasis in NIFTP and the need for a case by case analysis and continuing post-operative follow-up for detection of residual or recurrent disease.

HBME1 and CK19 expression in non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) vs other follicular patterned thyroid lesions.

BACKGROUND: Thyroid neoplasms with follicular architecture can have overlapping morphologic features and pose diagnostic confusion among pathologists. Various immunohistochemical stains have been investigated as potential diagnostic markers for PTC, among which HBME1 and CK19 have gained popularity. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) poses similar diagnostic challenges with interobserver variability and is often misdiagnosed as adenomatoid nodule or follicular adenoma. This study aims to evaluate expression of HBME1 and CK19 in NIFTPs in comparison to other well-differentiated thyroid neoplasms and benign mimickers. METHOD: Seventy-three thyroid cases diagnosed over a period of 3 years at Methodist University Hospital, Memphis, TN, USA, were included in this study: 9 NIFTP; 18 papillary thyroid carcinoma (PTC); 11 follicular variant of papillary thyroid carcinoma, invasive (I-FVPTC); 24 follicular adenomas (FA); and 11 multinodular goiters/adenomatoid nodules (MNG). A tissue microarray (TMA) was constructed and HBME1 and CK19 immunohistochemistry was performed. RESULTS: 77.8% of NIFTPs, 88.9% of PTCs, 81.8% of I-FVPTCs, 16.7% of FAs, and 18.2% of MNGs showed HBME-1 expression. 66.7% of NIFTPs, 83.3% of PTCs, 81.8% of I-FVPTCs, 33.3% of FAs, and 45.4% of MNGs expressed CK19. Difference in expression of HBME1 and CK19 was statistically significant for NIFTP vs FA (qualitative; p < 0.05) and NIFTP vs MNG (p < 0.05). No statistically significant difference was found for HBME1 in NIFTP vs PTC (conventional and FVPTC), p ≥ 0.2. Sensitivity of HBME1 and CK19 for NIFTP were 78% and 67%, ~ 88% each for PTC, and 89% and 100% for FVPTC, respectively, while specificity of HBME1 and CK19 for NIFTP were 53% each, ~ 62% each for PTC, and ~55% each for FVPTC. CONCLUSION: Our study indicated that HBME1 and CK19 are valuable markers in differentiating NIFTPs from morphologic mimics like follicular adenoma and adenomatoid nodules/multinodular goiter. While HBME1 and CK19 are both sensitive in diagnosing lesions with PTC-like nuclear features, CK19 stains a higher number of benign lesions in comparison to HBME1. No increase in sensitivity or specificity in diagnosis of NIFTP, PTC, or FVPTC was noted on combining the two antibodies.

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.

[Diagnostic principles of thyroid tumors in pathology : Relevant changes due to the current WHO classification]. / Diagnostische Grundlagen von Schilddrüsentumoren in der Pathologie : Relevante Änderungen durch die aktuelle WHO-Klassifikation.

The current edition of the WHO classification of thyroid tumors (2017) contains a number of very relevant changes with considerable consequences for the diagnostic assessment of thyroid specimens. This applies to both the histomorphological examination of surgical specimens and the preoperative fine needle biopsy (FNB). In addition, molecular pathological examinations are becoming increasingly important in the diagnosis of thyroid tumors. Changes affect practically all areas of thyroid tumor diagnostics. Some of these changes have far-reaching consequences that justify a comprehensive commentary and query of the knowledge acquired in the form of this CME article.

Immunohistochemistry Helps to Distinguish Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features/Noninvasive Encapsulated Follicular Variant of Papillary Thyroid Carcinoma with Other Follicular Thyroid Lesions.

Background and Objectives: We aimed to assess the diagnostic value of various immunohistochemical (IHC) markers and panels for differentiation among benign follicular nodules (BFNs), noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs), noninvasive encapsulated follicular variants of papillary thyroid carcinoma (NEFVPTCs), and infiltrative FVPTC (IFVPTC). Materials and Methods: Sixty-three cases were classified as BFNs, NIFTPs, NEFVPTCs, or IFVPTCs and were evaluated using the following markers: CK19, CD56, galectin-3, CITED1, HBME-1, VE1, and TROP-2. Results: The IHC results for NIFTP and NEFVPTC exhibited no statistically significant differences. In differentiating IFVPTCs from BFNs and NIFTPs/NEFVPTCs, galectin-3 and TROP-2 were the markers with the highest sensitivity plus high specificity, respectively. In various combinations, panel co-expression of two markers, including galectin-3 and/or HBME-1 and/or TROP-2, and the combination of galectin-3 and TROP-2 co-expression could achieve 100% in all aspects. In terms of discrimination of BFNs from NIFTP/NEFVPTC, CK19 was the single most sensitive marker (81.3%), while CD56 was the most specific (100%). The panel consisting of CK19 and/or HBME-1 exhibited the greatest sensitivity (96.9%), but the panel with CD56 and/or HBME-1 exhibited the greatest specificity (90.5%). Conclusions: Our results broaden the use of IHC markers for differential diagnoses among the four groups of follicular-based lesions. In addition, the similar IHC profiles of NIFTP and NEFVPTC also suggest the original criterion of <1% papillae within tumors, providing a reliable NIFTP diagnosis. Their close relationship may represent a spectrum of progressing neoplasia.

Impact of Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features on Revised Bethesda System Malignancy Rates at a Single Institution.

BACKGROUND: The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) standardizes thyroid cytopathology reporting in six tier diagnostic categories. In recent years, noninvasive encapsulated follicular variant of papillary thyroid carcinoma was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). This study examines the impact of NIFTP on the BSRTC risk of malignancy (ROM). METHODS: This was a retrospective review of prospectively collected data from 565 patients who underwent fine needle aspiration and thyroidectomy at a single institution. ROM for each Bethesda category was analyzed and calculated with NIFTP classified as a malignant and nonmalignant lesion. Absolute and relative differences between ROM were compared. RESULTS: Of 565 patients, 19 were Bethesda I, 159 were Bethesda II, 178 were Bethesda III, 46 were Bethesda IV, 42 were Bethesda V, and 121 were Bethesda VI. ROM differences with NIFTP classified as malignant versus nonmalignant for each class were as follows: Bethesda I, no change; Bethesda II, 18%-14%; Bethesda III, 55%-48%; Bethesda IV, 50%-35%; Bethesda V, 93%-91%; and Bethesda VI, 99%-98%. Absolute ROM differences for each category were as follows: Bethesda I, 0%; Bethesda II, 4%; Bethesda III, 7%; Bethesda IV, 15%; Bethesda V, 2%; and Bethesda VI, 1%. CONCLUSIONS: A decreasing trend in absolute and relative ROM was seen in Bethesda II, III, and IV categories; however, exclusion of NIFTP as a malignant lesion did not significantly alter the ROM of BSRTC categories. Surgeons should assess their respective institution's experiences with NIFTP and the BSRTC.

Ultrasound findings of noninvasive follicular thyroid neoplasm with papillary-like nuclear features compared with those of follicular variant of papillary carcinoma and encapsulated papillary carcinoma: a single-institution study in Japan.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a new entity adopted by the newest World Health Organization classification. It is differentiated from follicular variant papillary thyroid carcinoma (FVPTC) and regarded as non-malignant disease. Here, we compared the ultrasound findings of NIFTP (n = 40) with those of FVPTC (n = 94) and encapsulated PTC (encap-PTC) (n = 157). The NIFTP group showed benign findings on ultrasound significantly more frequently than the FVPTC group based on the Japan Society of Ultrasonics in Medicine criteria: a regular shape (p < 0.001), well edge definition (p = 0.007), smooth character (p < 0.001), isoechoic and homogeneous internal echoes (p < 0.001), lack of punctate microcalcification (p = 0.027), and a regular marginal hypoechoic zone (p < 0.001). Compared to encap-PTC, NIFTP has a significantly higher incidence of benign findings: isoechoic and homogeneous internal echoes (p < 0.001), lack of punctate microcalcification (p < 0.001), and a regular marginal hypoechoic zone (p = 0.004). Based on the ultrasound classification (USC) system at Kuma Hospital, no cases were classified as malignant (USC ≥3.5), but 55.4% of the FVPTCs and 53.5% of the encap-PTCs were diagnosed as malignancy. However, on cytology, the incidence of NIFTP classified as Bethesda-V or -VI (PTC) was very high at 86.9%. All patients underwent surgical treatment, but none of the NIFTP patients showed postoperative recurrence. Although avoiding surgery might be difficult because of the high incidence of malignant cytology, overtreatment (including extensive surgery) for NIFTP can be avoided by paying close attention to the lack of malignant findings on ultrasound.

Prevalence and diagnostic significance of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among tumors previously diagnosed as follicular adenoma: a single-institutional study in Japan.

The incidence of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in papillary thyroid carcinoma (PTC) is significantly lower in Asian countries than Western countries; however, the difference remains unexplained. This study aimed to evaluate the incidence of NIFTP in tumors diagnosed as follicular adenoma (FA) in a Japanese institution and discuss the significance of NIFTP. In this study, 44 tumors were investigated, which were histologically diagnosed as FA at the Kuma Hospital in 2008. Of the 44 tumors, 13 (29.5%) were revised as NIFTP. In the remaining 31 tumors, the FA diagnosis was reconfirmed. On aspiration cytology, most of the NIFTPs were categorized into follicular neoplasm or suspicious for a follicular neoplasm. On histological examination, 9 (29.0%) of 31 FA nodules showed a nuclear score of 1. Twelve (92.3%) of 13 NIFTP nodules showed a nuclear score of 2, and the remaining nodule had a nuclear score of 3. No metastasis of FA or NIFTP was detected. There were no evidences of distant metastasis during follow-up. This is the first study to describe that NIFTP is more frequently included in tumors diagnosed as FA rather than PTC in Japan. As clinical management of FA and NIFTP is the same, in Japan, there is no reason to distinguish between FA and NIFTP. Conclusively, the necessity of using the disease entity "NIFTP" is not found in Japan.

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.

Invasion in thyroid cancer: Controversies and best practices.

Invasion is a key feature of malignancy and an important element in the classification, risk-stratification, and staging of thyroid cancers. However, the histopathologic criteria for tumor capsular invasion, angioinvasion, and extrathyroidal extension (ETE) have varied among pathologists, both in practice as well as in studies assessing the clinical significance of these findings. In this review, we provide historic context for the controversies surrounding the definition of invasion in thyroid neoplasms and highlight recent efforts to standardize how pathologists report capsular invasion, angioinvasion, and ETE. We offer practical suggestions for distinguishing invasion from its mimics and provide an algorithmic approach for classifying thyroid tumors based on integration of tumor invasiveness, nuclear atypia, and architectural pattern.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is rare, benign lesion using modified stringent diagnostic criteria: Reclassification and outcome study.

BACKGROUND: Rigid diagnostic criteria for NIFTP have been recently proposed. The frequency of NIFTP using the new criteria is unknown, and whether abortive papillae are associated with BRAFV600E mutation has not been studied. The aim of this study is to identify NIFTP by a retrospective review of Follicular Variant of Papillary Thyroid Carcinoma (FVPTC), and to study its incidence as well as the association between immunohistochemical BRAFV600E expression and abortive papillae in NIFTP. DESIGN: Thyroid tumors diagnosed as FVPTC or NIFTP over a period of 18 years (2000-2017) were identified using the laboratory information system. The final pathology reports were reviewed and potential NIFTP were retrieved. The archived slides for these cases were independently reviewed by 2 pathologists. BRAFV600E (clone: VE1) immunostain was performed on representative tumor blocks. Clinical information including follow-up data was obtained from the electronic medical records. RESULTS: Among the 1918 cases with the diagnosis of papillary thyroid carcinoma (PTC), 589 (30.7%) of FVPTC and 136 cases of potential NIFTP were identified. After the review of the archived pathology slides, 29 lesions were morphologically reclassified as NIFTP. Four (13.7%) of these were positive for BRAFV600E; no association was found between the presence of abortive papillae and BRAFV600Eexpression (p=0.3). Exclusion of the 4 cases with BRAFV600Eexpression resulted in 25 lesions of final NIFTP, representing 4.2% of the FVPTC and 1.3% of the PTC. The mean age of the NIFTP patients was 50 years, 87.5% were females. The mean size of the lesions was 1.4 cm (0.1-4.0 cm). Intranuclear pseudoinclusions were not identified, and abortive papillae were identified in 60% of NIFTP. The average follow-up was 70 (28-166) months. There were no adverse events (recurrence or metastasis) in the NIFTP group. CONCLUSION: When strictly defined, NIFTP comprises 1.3% of cases perviously classified as PTC. In morphological NIFTP, no correlation is found between the presence of abortive papillae and the BRAFV600E expression. Intranuclear pseudo-inclusions are not observed in NIFTP. Modification of current morphological criteria to include BRAFV600E immunohistochemistry test may stratify NIFTP with benign outcome.

Non Invasive Follicular Thyroid Neoplasm with Papillary like nuclear features (NIFTP), A time for change in Pakistan.

OBJECTIVE: To determine the cases of Noninvasive Follicular thyroid neoplasm with papillary like nuclear features (NIFTP) in Pakistani population retrospectively. Another objective was to determine their clinical and radiological outcomes with respect to local and systemic disease recurrence, reconfirming the benign course of this new nomenclature in Thyroid tumors by WHO in our population would encourage adopting the new conservative treatment approach in such patients. METHODS: This is a retrospective cohort study conducted at a tertiary care center in Karachi, Pakistan from 2007-2016. All follicular Variant papillary thyroid cancer (FVPTC) reported from a single institute had their histopathology slides reexamined for diagnosing NIFTP as per the new WHO criteria. These cases were then followed retrospectively from their diagnosis onset through their medical and electronic health record for any local or systemic disease recurrence. RESULTS: There were 199 cases of Papillary Thyroid cancer (PTC) which included 22 cases of FVPTC. Eleven cases fulfilled NIFTP criteria with tumor size ranging from 1.1cm to ≥ 5.5cm. All patients in the NIFTP group underwent total thyroidectomy. Nine patients (81.81%) received RAI131 therapy. Four (45%) patients had a median follow up of three to four years. There was no disease recurrence seen on both ultrasound and RAI scans of patients in the NIFTP group. Seven patients (87.5%) had normal surveillance thyroglobulin levels except one whereas three patients were lost to follow up. There was no disease recurrence seen both radiologically and biochemically in the NIFTP group. CONCLUSION: Our study favors the low risk nature of NIFTP with no disease recurrence in the cases studied and encourages de-escalation of treatment.

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC): A report of 2,781 cases in a Chinese population.

OBJECTIVE: To evaluate the diagnostic utility of The Bethesda System for Reporting Thyroid Cytology (TBSRTC) at Peking University Cancer Hospital, the incidence of noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP), and the impact of reclassification on cytopathological outcomes. METHODS: We performed a retrospective study of thyroid fine-needle aspiration (FNA) cases between April 2014 and March 2019. The FNA results were classified according to TBSRTC. Post-surgery histological findings were followed up. RESULTS: A total of 2,781 thyroid FNAs were performed. The incidences of the 6 diagnostic categories (DCs I-VI) were 14.8%, 17.1%, 15.8%, 2.3%, 11.6% and 38.5%, respectively. A total of 1,122 patients (40.3%) had corresponding histological results. NIFTP accounted for 0.4% of papillary thyroid carcinoma (PTC) cases, and there was no significant difference in the risk of malignancy (ROM) for each TBSRTC DC between "NIFTP=carcinoma (Ca)" and "NIFTP≠Ca". When "NIFTP=Ca", the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of TBSRTC were 98.0%, 84.0%, 99.4%, 58.3%, and 97.5%, respectively. When "NIFTP≠Ca", the sensitivity, specificity, PPV, NPV and accuracy of the TBSRTC were 98.1%, 81.5%, 99.3%, 61.1%, and 97.5%, respectively. CONCLUSIONS: TBSRTC is effective in the preoperative diagnosis of thyroid nodules in Peking University Cancer Hospital. The impact of the reclassification of NIFTP on cytopathological outcomes is limited because of its low incidence, and the revised ROMs are not suitable for Asian patients.