Struma ovarii and peritoneal strumosis during pregnancy.

BACKGROUND: Struma ovarii is a special type of ovarian dermoid cyst and accounts for approximately 2-3 % of all dermoid tumours. Benign struma ovarii may manifest as distant metastasis, called peritoneal strumosis, which makes it biologically similar to malignancy, and has been reported in limited cases but never discovered during pregnancy. CASE PRESENTATION: We report a patient with a history of right struma ovarii cystectomy. During pregnancy, pelvic masses with non-specific clinical presentation were found again. During the caesarean section, contralateral struma ovarii with dissemination of nodules in the peritoneal cavity was found, and pathology revealed that the masses were thyroid follicle ovarian goitres. DISCUSSION AND CONCLUSIONS: Recurrent benign struma ovarii with extraovarian dissemination is a rare aggressive clinical manifestation different from malignancy. It is emphasized that adequate assessment and complete resection of suspicious masses are of great importance.

Deep learning prediction of BRAF-RAS gene expression signature identifies noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RAS mutations, rather than BRAFV600E mutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor's expression profile resembles a BRAFV600E or RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P < 0.0001). To test the hypothesis that BRS may serve as a surrogate for biological processes that determine tumor subtype, a separate model was trained on TCGA slides to predict BRS as a linear outcome. This model performed well in cross-validation on the training set (R2 = 0.67, dichotomized AUC = 0.94). In our internal cohort, NIFTPs were near universally predicted to have RAS-like BRS; as a sole discriminator of NIFTP status, predicted BRS performed with an AUC of 0.99 globally and 0.97 when restricted to follicular-patterned neoplasms. BRAFV600E-mutant PTC-EFG had BRAFV600E-like predicted BRS (mean -0.49), nonmutant PTC-EFG had more intermediate predicted BRS (mean -0.17), and NIFTP had RAS-like BRS (mean 0.35; P < 0.0001). In summary, histologic features associated with the BRAF-RAS gene expression spectrum are detectable by deep learning and can aid in distinguishing indolent NIFTP from PTCs.

Long-term follow-up of differentiated thyroid carcinoma in children and adolescents.

Objectives The aims were to analyze the clinical features, response to treatment, prognostic factors and long-term follow-up of children and adolescents with differentiated thyroid carcinoma (DTC). Methods Eighty patients with DTC were studied retrospectively. All underwent total or near-total thyroidectomy, and in 75 cases, ablative iodine therapy was recommended. Patients were assessed periodically by tests for serum thyroglobulin levels and whole-body iodine scans. Age, gender, initial clinical presentation, histology, tumor stage, postoperative complications, radioiodine treatment protocol, treatment response, thyroglobulin (Tg), recurrence and long-term disease progression were evaluated. Results Seventy patients completed >2 years of follow-up (23 males, 47 females; median age: 14 years; range: 3-18 years). Sixty-two patients showed papillary DTC and eight, follicular DTC. Sixty-five percent presented nodal metastasis and 16%, pulmonary metastasis at diagnosis. Six months after first radioiodine treatment, 36.2% of patients were free of disease. Seven recurrences were documented. At the end of follow-up, overall survival was 100%, and 87.2% of patients were in complete remission. Nine patients had persistent disease. We found a significant association between stage 4 and persistent disease. Hundred percent of patients with negative Tg values at 6 months posttreatment were documented free of disease at the end of the follow-up. The analysis of disease-free survival based on radioiodine treatment protocols used showed no statistically significant differences. Conclusions DTC in children and adolescents is frequently associated with presence of advanced disease at diagnosis. Despite this, complete remission was documented after treatment in most cases, with a good prognosis in the long-term follow-up. Negative posttreatment thyroglobulin and stage 4 at diagnosis were significant prognostic variables.

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.

[Hereditary predispositions to follicular thyroid tumors]. / Prédispositions héréditaires aux tumeurs thyroïdiennes de souche folliculaire.

Familial thyroid cancers of follicular origin are rare and include syndromic and non-syndromic tumours. In familial adenomatous polyposis, the prevalence of papillary thyroid cancer is 2-12% and in 20-40% of cases it is a cribriform-morular papillary thyroid carcinoma. Morules and cribriform pattern are the two main typical criteria, associated with a nuclear and cytoplasmic immunopositivity for beta catenin. DICER1 syndrome is associated with pleuropneumoblastoma, ovarian tumors and thyroid pathology (multinodular goiter and less frequently a well-differentiated thyroid cancer without microscopic particularity). Cowden syndrome is characterized by multiple hamartomas and two-thirds of patients develop thyroid pathology, including multinodular goiter (50-67%) and cancer (35%), the latter being one of the major diagnostic criteria of the syndrome. Classic triad of Carney complex associates lentiginosis, myxoid tumors, and various endocrine abnormalities; thyroid pathology occurs in 10% of cases and may be benign or malignant. In Werner's syndrome, thyroid cancer is present in 18% of cases. McCune-Albright syndrome is characterized by fibrous dysplasia, café-au-lait spots and various endocrinopathies including hyperthyroidism and nodular hyperplasia. Non-syndromic thyroid cancers, which represent the majority of familial cancers, are most often papillary carcinomas. In daily practice, in the presence of multiple benign thyroid nodules and/or thyroid cancer in a young person, or with family thyroid diseases, the pathologist should be aware about hereditary predispositions to propose an oncogenetic consultation.

A Comparative Study of ARHI Imprinted Gene Detection and Fine-Needle Aspiration Cytology in the Differential Diagnosis of Benign and Malignant Thyroid Nodules.

Aims: To compare fine-needle aspiration cytology (FNAC) with imprinted gene detection in the differential diagnosis of benign and malignant thyroid nodules. Methods: A total of 34 patients (35 cases of thyroid nodules) were examined using fine-needle puncture biopsy under ultrasound guidance, and the biopsy tissues were examined by cytologic examination and imprinted gene detection. Combined with postoperative pathology and follow-up results, the diagnostic value and consistency of the two methods were analyzed and compared. Results: The detection of benign and malignant thyroid nodules by ARHI imprinted gene had a high consistency with FNAC, and ARHI imprinted gene detection had a higher detection rate, sensitivity, and accuracy. Conclusions: Imprinted gene detection has high accuracy and sensitivity in the differential diagnosis of benign and malignant thyroid nodules. It provides a scientific reference for clinical treatment and should be incorporated into diagnostic protocols for thyroid tumor.

Systematic Review and Meta-analysis of the Impact of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP) on Cytological Diagnosis and Thyroid Cancer Prevalence.

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.

Risk of Malignancy According to the Sub-classification of Atypia of Undetermined Significance and Suspicious Follicular Neoplasm Categories in Thyroid Core Needle Biopsies.

The objective of this study was to evaluate the risk of malignancy (ROM) associated with atypia of undetermined significance (AUS) and suspicious follicular neoplasm (SFN) core needle biopsy (CNB) categories after further sub-classification. Data from 2267 thyroid nodules evaluated by ultrasound-guided CNB, from January to December 2015, were retrospectively reviewed. AUS nodules (n = 556) were sub-classified as follows: (1) architectural atypia (AUS-A; n = 369, 66.4%), (2) cytologic atypia (AUS-C; n = 35, 6.3%), (3) cytologic/architectural atypia (AUS-C/A; n = 85, 15.3%), or (4) oncocytic atypia (AUS-O; n = 67, 12.1%). SFN nodules (n = 172) were sub-classified as follows: (1) architectural atypia only (SFN-A; n = 110, 64%), (2) cytologic/architectural atypia (SFN-C/A; n = 24, 14%), or (3) oncocytic atypia (SFN-O; n = 38, 22%). Diagnostic surgery was performed in 162 (30.2%) AUS cases and 105 (61%) SFN cases. The ROM of each sub-category was evaluated. The overall ROM was 15.3-52.5% in AUS nodules and 35.5-58.1% in SFN nodules. The ROM was higher in the AUS-C (22.9-88.9%) and AUS-C/A (32.9-90.3%) groups than AUS-A (11.9-40%) and AUS-O (7.5-41.7%). In the SFN category, ROM in the SFN-C/A group was also higher than SFN-A or SFN-O (37.5-75%, 40-57.9%, and 21.1-47.1%, respectively). Our study shows that the ROM was higher in AUS or SFN sub-categories with cytologic atypia than those without cytologic atypia. Because of the heterogeneous nature of AUS and SFN categories, sub-classification may be a more effective approach for risk stratification, allowing optimal management of patients with thyroid nodules.

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): Update and Diagnostic Considerations-a Review.

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.

Modified Transverse-Vertical Gross Examination: a Better Method for the Detection of Definite Capsular Invasion in Encapsulated Follicular-Patterned Thyroid Neoplasms.

The diagnosis of encapsulated follicular-patterned thyroid carcinoma (EFPTC) is challenging, and the detection of capsular invasion and/or vascular invasion is essential in distinguishing benign lesions from malignant lesions. In this study, we present a modified transverse-vertical gross examination method with additional vertical cuts at the upper and lower ends of thyroid nodules. In addition, we compared the clinicopathological characteristics of patients with EFPTC between conventional and modified methods. The diagnostic rate of follicular thyroid carcinoma and invasive encapsulated follicular variant of papillary thyroid carcinoma was higher with the modified method (p = 0.003 and p = 0.028, respectively). Furthermore, the paraffin block number and the number of capsular invasion per centimeter were significantly higher with the modified method (p < 0.001 and p = 0.007, respectively). However, vascular invasion was not significantly different between the two methods (p = 0.771). The possibility of identifying capsular invasion was around two times higher with the modified method (odds ratio = 1.91, 95% confidence interval = 1.20-3.07, p = 0.007). A total of 38 samples (23%) in the modified transverse-vertical group had capsular and/or vascular invasion in the additional vertical cuts of the upper/lower ends of the tumor. Our modified transverse-vertical gross examination method was more effective than the conventional transverse examination method for the detection of capsular invasion in EFPTC. This modified gross examination method might allow a better differential diagnosis among various encapsulated micro-follicular proliferative lesions.

Diagnostic value of HBME-1, CK19, Galectin 3, and CD56 in the subtypes of follicular variant of papillary thyroid carcinoma.

Our aim is to explore differences in Hector Battifora mesothelial-1 (HBME-1), cytokeratin-19 (CK19), Galectin-3 (Gal-3), and CD56 expression in infiltrative follicular variants of papillary carcinoma (IFVPTC) and encapsulated follicular variants of papillary carcinoma (EFVPTC) and to provide clues for distinguishing the two subtypes preoperatively. Tissue microarrays from 100 EFVPTC (45 non-invasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) and 55 invasive EFVPTCs), 43 IFVPTCs, and 64 follicular neoplasms (FN) were immunostained with HBME-1, CK19, Gal-3, and CD56. Each case was scored 1 point for every positive result. Immunohistochemical expression was not significantly different in invasive EFVPTC and NIFTP, except for that of HBME-1. HBME-1, CK19, Gal-3, and CD56 expression were significantly higher in IFVPTC than in EFVPTC. At the cutoff of 3 points, the score method had special diagnostic value for differentiating IFVPTC from EFVPTC and FN and for predicting lymph node metastasis. Scoring of immunohistochemistry results may be applied to core biopsy or cell blocks to assist ultrasonographic, cytologic and molecular tests in differentiating IFVPTC and EFVPTC preoperatively, possibly appropriately guiding EFVPTC preoperatively for limited operation or active surveillance.

Cytomorphological Analysis of Thyroid Nodules Diagnosed as Follicular Variant of Papillary Thyroid Carcinoma: a Fine Needle Aspiration Study of Diagnostic Clues in 42 Cases and the Impact of Using Bethesda System in Reporting-an Institutional Experience.

Follicular variant of papillary thyroid carcinoma (FVPTC) is the second most common subtype of papillary thyroid carcinoma (PTC) after classical PTC (cPTC). Follicular thyroid lesions such as follicular adenomas/carcinomas, FVPTC, and noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) pose some diagnostic challenges for FNAC. In this study, we aimed to explore whether FNAC can demonstrate diagnostic clues by re-evaluating cytology slides from histopathologically diagnosed FVPTC cases. A total of 42 patients were enrolled in this study: patients were diagnosed with FVPTC via surgical resection between 2006 and 2016, and all patients were subjected to preoperative FNAC, which was conducted at either a private center or at the teaching hospital of Kocaeli University and reported by the same cytopathologist (NP). Clinical and cytomorphological characteristics were reviewed by both authors .Most cases (76.2%) are diagnosed either Bethesda IV or V. The majority of cases had a high cellularity (38/42; 90.5%), and the most frequent observations were monolayer and large syncytial groups of cells (95.2%). While microfollicular structures were observed in 30 (71.4%) cases, nuclear crowding and large naked nuclei were observed in all cases. Nuclear grooves were sparsely detected in 23 (54.8%) cases, and nuclear pseudoinclusions were detected in only six (14.3%) cases. Because thyrocytes often have a mixed architecture in FVPTC, despite a distinct follicular morphology, we believe that nuclear overcrowding, enlargement, and hyperchromasia in cases presenting with increased cellularity are notable clues for the cytodiagnosis of FVPTC. We believe that the primary aim of FNAC in such cases is to give preoperative diagnosis as either category IV or V. Nuclear crowding, monolayered clusters with large syncytial formations, nuclear enlargement, and hyperchromasia are notable cytomorphologic clues for the diagnosis of FVPTC on FNAC.

Does Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features (NIFTP) Have a Unique Molecular Profile?

OBJECTIVES: Recognizing preoperative characteristics of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is important for clinical management. Therefore, we assessed presurgical NIFTP molecular profiles using fine-needle aspiration (FNA) material. METHODS: Presurgical FNA reports of 39 surgically confirmed NIFTP cases from January 2013 through May 2017 were assessed for Afirma and ThyroSeq results. RESULTS: Twenty-one of 39 NIFTP nodules were preoperatively tested with Afirma with two benign and 19 suspicious results. Twenty-seven of 39 nodules were tested with ThyroSeq (nine of 39 had both Afirma and Thyroseq): 18 (67%) had RAS mutations (13 NRAS, four HRAS, one KRAS), and three of 18 had multiple alterations (NRAS + TP53, n = 1; NRAS + PTEN, n = 2). BRAF T599_R603 + EIF1AX mutation (n = 1), PTEN mutation (n = 1), MET overexpression (n = 1), PAX8/PPARG fusion (n = 3), and THADA/IGF2BP3 fusion (n = 3) comprised the remainder. CONCLUSIONS: NIFTP cases most commonly displayed suspicious Afirma results and RAS mutations on ThyroSeq, lacking aggressive/BRAF-V600E-like mutations. While NIFTP remains a surgical entity, the lack of aggressive/BRAF-V600E-like mutations can aid in determining the extent of surgery.

AHNS Series: Do you know your guidelines? AHNS Endocrine Section Consensus Statement: State-of-the-art thyroid surgical recommendations in the era of noninvasive follicular thyroid neoplasm with papillary-like nuclear features.

The newly introduced pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) will result in less bilateral thyroid surgery as well as deescalation in T4 suppressive and radioactive iodine treatment. Although, NIFTP is a nonmalignant lesion that has nuclear features of some papillary malignancies, the challenge for the surgeon is to identify a lesion as possibly NIFTP before the pathologic diagnosis. NIFTP, due to its reduction of overall rates of malignancy, will result in the initial surgical pendulum swinging toward lobectomy instead of initial total thyroidectomy. This American Head and Neck Society endocrine section consensus statement is intended to inform preoperative evaluation to attempt to identify those patients whose final pathology report may ultimately harbor NIFTP and can be offered a conservative surgical plan to assist in cost-effective, optimal management of patients with NIFTP.

Lingual Thyroid Carcinoma: A Case Report and Review of Surgical Approaches in the Literature.

INTRODUCTION: Lingual thyroid cancer is a rare entity with a paucity of literature guiding methods of surgical treatment. Its location presents anatomic challenges with access and excision. OBJECTIVE: We present a case of T4aN1b classical variant papillary thyroid carcinoma of the lingual thyroid that was removed without pharyngeal entry. We also present a review of the literature of this rare entity and propose a treatment algorithm to provide safe and oncologic outcomes. FINDINGS: Our review of the literature found 28 case reports of lingual thyroid carcinoma that met search criteria. The trans-cervical/trans-hyoid approach was the most frequently used and provides safe oncologic outcomes. This was followed by the transoral approach and then lateral pharyngotomy. Complications reported across the series include 1 case of pharyngocutaneous fistula associated with mandibulotomy and postoperative respiratory distress requiring reintubation or emergent tracheostomy in 2 patients. CONCLUSION: The location of lingual thyroid carcinoma can be variable, and surgical management requires knowledge of adjacent involved structures to decrease the risk of dysphagia and airway compromise. In particular, for cases where there is extensive loss to swallowing mechanisms, laryngeal suspension can allow the patient to resume a normal diet after treatment.

Morphology combined with ancillary techniques: An algorithm approach for thyroid nodules.

INTRODUCTION: Several authors have underlined the limits of morphological analysis mostly in the diagnosis of follicular neoplasms (FN). The application of ancillary techniques, including immunocytochemistry (ICC) and molecular testing, contributes to a better definition of the risk of malignancy (ROM) and management of FN. According to literature, the application of models, including the evaluation of ICC, somatic mutations (ie, BRAFV600E ), micro RNA analysis is proposed for FNs. This study discusses the validation of a diagnostic algorithm in FN with a special focus on the role of morphology then followed by ancillary techniques. METHODS: From June 2014 to January 2016, we enrolled 37 FNs with histological follow-up. In the same reference period, 20 benign nodules and 20 positive for malignancy were selected as control. ICC, BRAFV600E mutation and miR-375 were carried out on LBC. RESULTS: The 37 FNs included 14 atypia of undetermined significance/follicular lesion of undetermined significance and 23 FN. Specifically, atypia of undetermined significance/follicular lesion of undetermined significance resulted in three goitres, 10 follicular adenomas and one NIFTP whereas FN/suspicious for FN by seven follicular adenomas and 16 malignancies (nine non-invasive follicular thyroid neoplasms with papillary-like nuclear features, two invasive follicular variant of papillary thyroid carcinoma [PTC] and five PTC). The 20 positive for malignancy samples included two invasive follicular variant of PTC, 16 PTCs and two medullary carcinomas. The morphological features of BRAFV600E mutation (nuclear features of PTC and moderate/abundant eosinophilic cytoplasms) were associated with 100% ROM. In the wild type cases, ROM was 83.3% in presence of a concordant positive ICC panel whilst significantly lower (10.5%) in a negative concordant ICC. High expression values of MirR-375 provided 100% ROM. CONCLUSIONS: The adoption of an algorithm might represent the best choice for the correct diagnosis of FNs. The morphological detection of BRAFV600E represents the first step for the identification of malignant FNs. A significant reduction of unnecessary thyroidectomies is the goal of this application.

Molecular Testing of Nodules with a Suspicious or Malignant Cytologic Diagnosis in the Setting of Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP).

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.

Identification of Two Distinct Molecular Subtypes of Non-Invasive Follicular Neoplasm with Papillary-Like Nuclear Features by Digital RNA Counting.

BACKGROUND: The follicular variant (FV) of papillary thyroid cancer (PTC) is one of the most common variants of PTC. Clinically, non-infiltrative FVPTC is considered a low-risk variant of PTC, and the non-invasive encapsulated forms of FVPTC represent a group of thyroid tumors with a particularly good prognosis. Consequently, these neoplasms have been very recently reclassified as non-invasive follicular neoplasms with papillary-like nuclear features (NIFTP). From a molecular standpoint, NIFTP appears to be similar to follicular neoplasms. However, only limited data are currently available regarding their gene expression profile. METHODS: The aim of this study was to identify specific molecular signatures of 26 NIFTPs compared to those of 19 follicular adenomas (FAs) and 18 infiltrative FVPTCs (IFVPTCs). A nanoString custom assay was used to perform mRNA expression analysis. All cases were also genotyped for BRAF, N-, H-, and K-RAS mutations. Samples were grouped on the basis of gene expression profiles by Pearson's correlation and non-negative matrix factorization clustering analysis. Finally, the uncorrelated shrunken centroid machine-learning algorithm was used to classify the samples. RESULTS: The results revealed distinct expression profiles of FAs and IFVPTCs. NIFTP samples can exhibit different expression profiles, more similar to FAs (FA-like) or to IFVPTCs (IFVPTC-like), and these different expression profiles largely depend on the presence of different mutations (RAS or BRAF). CONCLUSION: In conclusion, although further validation of the model is required by using a larger group of prospective cases, these data reinforce the hypothesis that IFVPTC-like NIFTPs might represent precursors of IFVPTC.