Follicular Variant Of Papillary Thyroid Carcinoma Research Articles

SUN-552 Ectopic Thymoma Masquerading as a Thyroid Mass

Background: Ectopic cervical thymomas are often confused with thyroid or parathyroid swellings due to their anatomical positioning (1). One of the rarest congenital abnormalities is intrathyroidal ectopic thymic tissue, cytologically confirmed in few reported cases (2). Fine Needle Aspiration Cytology in predominantly lymphocytic thymomas have also often been misinterpreted as Hashimoto's thyroiditis or malignant lymphoma (3). Clinical Case: We report a 12-year-old girl with ectopic cervical thymoma mimicking a thyroid mass. She was hospitalized with shortness of breath, swelling, facial flushing, weight loss, fatigue, and difficulty swallowing. Ultrasound and the MRI of the neck reported it to be an ectopic thyroid gland. CT scan of the neck and the chest reported the mass likely to be a thymoma that impinged on the carotid artery along with a mediastinal thymoma. Endocrine work up including complete blood count, PTH, gastrin, fasting glucose, insulin, thyroid function tests were all within normal limits. The patient underwent surgical resection of the mass and it was noted to be banana shaped, traversing from the neck into the mediastinum. Surgical pathology revealed well-defined thymic cortices and medullae, many Hassall corpuscles with admixed fat cells and thymic cyst lined by a layer of low columnar cells. The CD3 and Pax 5 immunostaining were positive for cells of thymic origin. Conclusion: Ectopic thymomas should be considered in the differential diagnosis of thyroid masses in children and adolescents. In such cases, apart from the clinical examination and the imaging studies, it is also important to perform the cytology and immunohistochemistry. Thyroid cell specific proteins such as thyroglobulin, thyroid transcription factor-1, thioperoxide and dipeptidyl aminopeptidase-4, neuroendocrine markers chromogranin, calcitonin and parathyroid hormone could be used to rule out cells of thyroid or parathyroid origin(4). Reference: 1. Thakur, A, et al. Ectopic cervical thymoma mimicking as papillary thyroid carcinoma: A diagnostic dilemma. Indian J Pathol Microbiol. 2010; 53; 305-307 2. Durmaz, et al. Intrathyroidal ectopic thymic tissue may mimic thyroid cancer: A case report. Journal of Pediatric Endocrinology and Metabolism. 2012; 25(9-10); 997-1000. 3. Lee YY, et al. Aspiration cytology of an ectopic cervical thymoma misinterpreted as a lymphoproliferative lesion of the thyroid: A case report. Oncol Lett. 2015; 10; 1255- 8. 4. De Micco C, et al, The value of thyroid peroxidase immunohistochemistry for preoperative fine-needle aspiration diagnosis of follicular variant PTC. Surgery. 1999; 126; 1200-4

The non-interventional approach to papillary thyroid microcarcinomas. An “active surveillance” dilemma

BackgroundRecent studies suggest that papillary-thyroid-microcarcinomas (PTMi) and follicular-variant-papillary-thyroid-cancers (FVPTC) are less aggressive overall. Our observations argue against. ObjectivesTo assess whether PTMi and FVPTC are indeed low-risk and could be safely followed without intervention. MethodsWe prospectively collected data of subjects with PTC on pathology post-thyroidectomy. Odds ratios (OR) were calculated with Fisher's exact test and differences between means were calculated using Mann Whitney's test. Results696 met inclusion-criteria; 436 had macrocarcinomas (PTMa) and 260 had PTMi. PTMa were statistically significantly more likely to present multifocal [44.0% vs.28.1%], with extrathyroidal extension [22.1% vs.3.4%], lymph nodes involvement [25.5% vs.8.8%] and local invasion [3.1% vs.0.4%] (p < 0.05 for all), but not with distant metastasis [3.4% vs.1.3%, p > 0.05]. Therefore, PTMi measuring down to 0.01 cm, harbored aggressive features. We also identified 174 cases with FVPTC and 522 subjects with non-FVPTC. FVPTC had lower incidence of multifocality [40.1%, vs.60.9%], extrathyroidal extension [8.6% vs.17.4%] and lymphatic involvement [5.2% vs.24.0%], but not distant metastasis or local invasion [p > 0.05 for all]. Therefore, FVPTC measuring down to 0.5 cm, also harbored aggressive features. ConclusionsPTMi and FVPTC aggressive features are substantial enough to require careful evaluation, independent of their original tumor size before defaulting to just “active surveillance.“

Abstract #554 A Rare Case of Aggressive Follicular Variant Papillary Thyroid Carcinoma with NRAS Mutation

Abstract #554 A Rare Case of Aggressive Follicular Variant Papillary Thyroid Carcinoma with NRAS Mutation

Molecular Profile and Clinicopathologic Features of Follicular Variant Papillary Thyroid Carcinoma.

The non-invasive encapsulated follicular variant of papillary thyroid carcinoma (FVPTC) has an indolent clinical behavior. Recently, it was proposed that this tumor type should be reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). To characterize NIFTPs, we evaluated the molecular and clinicopathologic characteristics of each FVPTC subtype. This study enrolled 29 patients with FVPTC who underwent thyroidectomy between January 2007 and June 2017. They were classified as non-invasive encapsulated FVPTC (NIFTP, n = 10), invasive encapsulated FVPTC (n = 11), and infiltrative FVPTC (n = 8) by two independent pathologists. Genetic alterations were analyzed by targeted next-generation sequencing using formalin-fixed, paraffin-embedded tissue samples and the clinicopathologic characteristics were retrospectively reviewed. There was no difference in preoperative cytologic classification between NIFTPs and invasive encapsulated FVPTCs, whereas infiltrative FVPTC was more likely to be Bethesda class VI than the encapsulated type (50% versus 9.5%; P = 0.033). Lymph node metastasis was not found in NIFTPs. There was no BRAFV600E mutation in NIFTPs, whereas one of 11 invasive encapsulated FVPTCs and three of 8 infiltrative FVPTCs harbored BRAFV600E. RAS mutations were frequently detected in encapsulated FVPTCs (5 of 10 NIFTPs and 4 of 11 invasive encapsulated FVPTCs) but were only detected in one case of the infiltrative type. There were no differences in molecular or clinicopathologic profiles between non-invasive and invasive encapsulated FVPTCs, except for lymph node metastasis and the presence of BRAFV600E. NIFTP has favorable pathologic characteristics with a high frequency of RAS mutations.

Non-invasive follicular thyroid neoplasm with papillary-like nuclearfeatures (NIFTP): a review and update.

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

DICER1 somatic mutations strongly impair miRNA processing even in benign thyroid lesions.

The alteration of miRNA processing is a driver event in several tumors including thyroid cancer. In particular, somatic DICER1 mutations, reported in follicular-patterned lesions, are shared by benign as well as malignant tumors. In the present study, we investigated the effects of alterations in the miRNA processing genes on the miRNA profile.The study included 19 follicular adenomas (FAs) and 22 follicular variant of papillary thyroid carcinomas (FVPTCs). The mutational status in the hot spot regions of DICER1, DROSHA, TARBP2, DGCR8 and the most commonly affected genes in thyroid tumors was investigated on both tumor and paired normal tissues. The miRNA profile and the mRNA expression levels of DICER1, DROSHA, TARBP2, DGCR8 and XPO5 were also evaluated.Two DICER1 RNase IIIb domain mutations were found in FAs. These lesions presented a considerable loss of 5p miRNAs. Fifteen miRNAs were specifically deregulated in DICER1-mutant lesions compared to FAs and FVPTCs. These miRNAs regulate crucial pathways in cancer such as Hippo, p53 and TGF-beta signalling.DICER1 somatic mutations in the RNase IIIb domain are not specific for malignancy, but the miRNA imbalance that they cause is remarkable, especially with regard to the loss of 5p miRNAs. DICER1-mutant lesions have a characteristic miRNA deregulation, which is different from that of FVPTCs; nevertheless, this impairment is consistent with malignant transformation. Further studies providing the real risk of malignancy associated with DICER1 mutations and the evolution of DICER1-mutant lesions are needed to make them useful in the clinical practice.

Histopathology of Encapsulated Follicular-Patterned Thyroid Tumors

Abstract Encapsulated follicular-patterned thyroid tumors remain diagnostically challenging for pathologists, including experts. The differential diagnosis typically includes hyperplastic/adenomatous nodule, follicular adenoma, follicular thyroid carcinoma, and follicular variant of papillary thyroid carcinoma (FVPTC). Noninvasive follicular thyroid neoplasm with papillary-like features is a new terminology that was recently proposed for a subset of noninvasive FVPTC that has a highly favorable outcome and can be treated in a conservative manner. This is in contrast to invasive-encapsulated FVPTC that clinically behaves similar to follicular thyroid carcinoma and infiltrative FVPTC that behaves like classic PTC. In this review, the differential diagnosis of encapsulated follicular-patterned thyroid neoplasms is discussed, including noninvasive follicular thyroid neoplasm with papillary-like features and its recently revised pathologic criteria. Commonly encountered diagnostic challenges and pitfalls are also reviewed, including criteria for capsular and vascular invasion and minimal diagnostic features of papillary thyroid carcinoma.

Prognosis of High-Risk Papillary Thyroid Cancer Patients with Pre-Ablation Stimulated TG

The prevalence of undetectable pre-ablation stimulated thyroglobulin (s-Tg) and its clinical implications in high-risk papillary thyroid cancer (PTC) patients remain poorly described. We investigated the rate of tumor recurrence in PTC patients initially classified as high risk but with pre-ablation s-Tg <1 ng/mL and negative anti-Tg antibody (TgAb). In order to have a follow-up period of at least 5 years for each patient, PTC patients consecutively seen at our department from May 2008 to June 2013 with the following characteristics were selected: (i) classified as American Thyroid Association high risk on the basis of tumor histopathologic features; (ii) submitted to adjuvant 131I therapy after total thyroidectomy; (iii) a postoperative pre-ablation s-Tg <1 ng/mL and negative TgAb. Among 767 high-risk PTC patients submitted to adjuvant 131I therapy, 69 patients met the inclusion criteria. Sixty-seven patients (97.1%) were diagnosed as classical PTC, and the remaining 2 patients (2.9%) were diagnosed as follicular variant PTC. When evaluated 9 to 12 months after 131I therapy, 67 patients (97.1%) were classified as excellent response. Two (2.9%) patients had an s-Tg >1 ng/mL (<3 ng/mL) in the absence of apparent disease, as detected by imaging methods (indeterminate response). During a median follow-up duration of 5.6 years, recurrence was observed in only 2 (2.9%) patients. The 67 (97.1%) patients without tumor recurrence were not submitted to any additional therapy, and all had a suppressed Tg <1 ng/mL in the last assessment. High-risk PTC patients with pre-ablation s-Tg <1 ng/mL and negative TgAb had a favorable prognosis. CT = computed tomography; L-T4 = levothyroxine; PTC = papillary thyroid cancer; SPECT/CT = single photon emission computed tomography/computed tomography; s-Tg = stimulated thyroglobulin; T4 = thyroxine; TgAb = anti-thyroglobulin antibody; US = ultrasound.

Interobserver and intraobserver variation in the morphological evaluation of noninvasive follicular thyroid neoplasm with papillary-like nuclear features in Asian practice.

To evaluate the current diagnostic criteria in reporting nuclear features of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), nine Asian pathologists with expertise in thyroid reviewed virtual slides of 30 noninvasive follicular patterned thyroid lesions according to the nuclear scoring system originally proposed by an international expert and a more detailed scoring system proposed by the Asian Working Group. The interobserver agreement for nuclear grading score was generally moderate (kappa value = 0.452). The best consistency fell on the chromatin features (kappa value = 0.658-1.000). A fair to moderate interobserver agreement was demonstrated in the evaluation of nuclear elongation, nuclear overlapping, membrane irregularities and distribution of papillary thyroid carcinoma (PTC) type nuclear features. A slight agreement was rendered for the evaluation of the nuclear enlargement. Intraobserver agreement was substantial to perfect when comparing results of both scoring systems. However, both scoring systems were not able to reliably separate NIFTP from an encapsulated follicular variant PTC with minimal lymph node metastasis or BRAFV600E mutation. Although the three-point nuclear scoring system for the diagnosis of NIFTP is widely used in Asian practice, interobserver variation was considerable. Ancillary immunohistochemical or molecular testing might be helpful in differentiating NIFTP from true PTC.

Correlation of papillary thyroid carcinoma different subtypes BRAF mutation and ultrasonic characteristics

Objective To investigate the correlation of BRAF mutation frequency with cervical lymph node metastasis, and to compare the ultrasonic characteristics in patients with BRAF mutation in papillary thyroid carcinoma (PTC) different subtypes. Methods The tumor samples were collected from 139 PTC patients who underwent thyroidectomy. And they were classified by histological subtype into 3 groups: classic variant of papillary thyroid carcinoma (CVPTC) group(34 cases), follicular variant of papillary thyroid carcinoma (FVPTC) group(36 cases), tall cell variant (TCV) group(69 cases). The BRAF mutation frequency and the correlation with cervical lymph node metastasis among 3 groups were analyzed, then the ultrasonic characteristics with BRAF mutation in PTC different subtypes were compared. Results ①The frequency of BRAF mutation was statistically significant different in different subtypes(χ2=6.390, P=0.041), and the frequency in TCV was 86.9%. There was also a statistical difference between BRAF mutation frequency and cervical lymph node metastasis among three subtypes (χ2=13.106, P=0.041). ②There was no statistically significant difference among the three groups in nodule number, echo level, internal structure, boundary, crossbar, morphology and acoustic halo of patients with BRAF mutation (P>0.05). ③A single factor analysis was performed for the ultrasonographic characteristics of patients with BRAF mutation, and there were significant statistical differences among the 3 groups in calcification type (χ2=21.7, P=0.001) and close to the envelope (χ2=7.726, P=0.021). ④Multivariate logistic regression showed that BRAF mutation was an independent influence factor affecting the calcification type of different histological subtypes in PTC patients. Conclusions ①BRAF mutation is correlated with cervical lymph node metastasis in different PTC subtypes. ②BRAF mutation is an independent influence factor affecting the morphology type of different calcification subtypes in PTC. The CVPTC group is mainly microcalcification, and the TCV group is mainly macrocalcification. Key words: Ultrasonography; Papillary thyroid carcinoma; Subtypes; BRAF gene

Diagnostic pitfalls and therapeutic outcomes of the macrofollicular variant of papillary thyroid carcinoma

BackgroundThe macrofollicular variant of papillary thyroid cancer (MFVPTC) is a rare histological variant of papillary thyroid cancer (PTC), with only 71 cases reported through 2014. This study analyzed the clinical, preoperative thyroid ultrasonography (US), and fine needle aspiration cytology (FNAC) features; and therapeutic outcomes of 11 patients with MFVPTC. MethodsThe records of 393 patients with histologically diagnosed follicular variant of papillary thyroid carcinoma (FVPTC), including 11 with MFVPTC, were retrospectively reviewed. Preoperative thyroid US findings, clinical presentation, treatment outcomes, and survival rates were analyzed. ResultMean tumor size was significantly greater in patients with MFVPTC than that in those with FVPTC (4.2 ± 2.1 cm vs. 2.9 ± 1.7 cm; p = 0.016). No patient with MFVPTC had lymph node involvement, but one had a micrometastasis to the lung, which responded well to therapeutic radioiodine. All MFVPTC lesions were isoechoic on US. Eight nodules had calcifications and eight had irregular margins. FNAC showed that these tumors had low cellularity, absence or focal presence of enlarged clear nuclei, and subtle or focal nuclear features of PTC. Cells were, arranged in microfollicular pattern, with abundant colloid background. Multifocal PTCs were detected in the opposite lobe of two patients. All 11 patients with MFVPTC had excellent outcomes. No patient experienced recurrence, and survival rates were high. ConclusionsMalignant US criteria combined with FNAC features have a low preoperative diagnostic rate for MFVPTC. Surgery is recommended for patients with thyroid nodules larger than 4 cm and those with subtle and focal atypical nuclei in FNAC.

Concomitant Thyroid Cancer in Patients with Multiple Endocrine Neoplasia Type 1 Undergoing Surgery for Primary Hyperparathyroidism.

Compared to those with sporadic primary hyperparathyroidism (SPHP), multiple endocrine neoplasia type 1 (MEN1) patients with primary hyperparathyroidism (MPHP) typically require more extensive dissection and have higher recurrence rates. Little is known about the risk of concomitant thyroid cancer in either setting. This study aimed to determine the rates and characteristics of thyroid cancer for MPHP versus SPHP patients undergoing parathyroidectomy. Patients with MPHP (diagnosed by clinical and/or genetic criteria) or SPHP who had initial or reoperative parathyroid exploration from 1967 to 2014 were identified via a prospective database. The thyroid cancer-specific data for MPHP patients (n = 29) were compared to a selected 2:1 age- and sex-matched SPHP cohort (n = 58) who all had concurrent thyroidectomy for any reason. Clinically significant thyroid cancer was defined as >1 cm in diameter. In the MPHP group, 24/29 (83%) thyroidectomies were preoperatively unplanned versus 20/58 (34%) in the SPHP matched cohort (p < 0.01), and in this setting there was no difference in the rate of histologic thyroid cancer (3/24 [13%] vs. 5/20 [25%], p = 0.44). Histologic thyroid cancer was identified in 8/29 (28%) MPHP versus 27/58 (47%) SPHP patients (p = 0.11). Despite observed differences in the time period and extent of thyroidectomy, MPHP patients did not have an increased likelihood of thyroid cancer (surgery before 2005: odds ratio [OR] = 2.57, p = 0.09; total thyroidectomy: OR = 5.47, p < 0.01; MPHP: OR = 1.14, p = 0.83). All MPHP thyroid cancers were characterized as conventional papillary thyroid cancer (PTC), while thyroid cancers in SPHP patients included both PTC (66%) and follicular-variant PTC (34%). No MPHP patient had clinically significant thyroid cancer compared to an incidence of 15/58 (26%) in SPHP patients (p < 0.01). Although patients with MEN1 have a substantial incidence of thyroid cancer (28%) and undergo more unplanned thyroidectomies during parathyroidectomy than do patients with SPHP, clinically significant thyroid cancer is proportionally uncommon.

A Population-Based Study on NIFTP Incidence and Survival: Is NIFTP Really a "Benign" Disease?

This study aimed to determine the incidence of noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP) in Ontario, Canada and the predictors of disease-free survival (DFS) by comparing patients with follicular variant papillary thyroid cancer (FVPTC) and patients with NIFTP. This population-based retrospective cohort study included all patients who had definitive surgery for well-differentiated thyroid cancer (WDTC) in Ontario, Canada between 1990 and 2001 and were followed until 2014. A conservative decision rule was applied to subtype-select FVPTCs into NIFTPs after pathology report review. The primary outcome was DFS, for which Cox proportional hazard regression analysis was performed to assess the impact of FVPTC versus NIFTP. At pathology re-review of the 725 FVPTC cases, 318 were reclassified as potential NIFTP. The median follow-up time was 15.3years for the entire cohort and 15.9years for those alive at the last follow-up visit. Disease failure occurred for 109 patients, 79 (19.4%) in the FVPTC group and 30 (9.4%) in the NIFTP group (p < 0.01). This effect was sustained in the multivariable analysis, with FVPTC showing significantly worse DFS than NIFTP (hazard ratio, 1.84; 95% confidence interval, 1.17-2.89). After recategorization of certain FVPTCs into NIFTPs, the findings showed that NIFTP accounted for 16.8% (1.461/8.699 per 100,000) of all WDTCs. The disease failure rate for NIFTP was 9.4%. The NIFTP diagnosis is challenging for the pathologist and may make tumor behavior difficult to predict for this entity. Caution should be used in the management of patients with an NIFTP.

Expression of HBME-1 and CD56 in follicular variant of papillary carcinoma in children: An immunohistochemical study and their diagnostic utility

Papillary thyroid carcinoma (PTC) is the most common differentiated thyroid cancer in children; and the follicular variant is the second most common variant after the classic subtype. The histological appearance of follicular variant of papillary thyroid cancer (FVPTC), can be mimicked by benign follicular nodules. Pediatric pathologists encountering such lesions with FVPTC-like appearance may err on diagnosing the benign lesions as malignant. In adult patients, several immunohistochemical markers have emerged recently as a useful adjunct to distinguish differentiated thyroid carcinomas from benign follicular lesions. We undertook an inter-institutional retrospective study to establish the diagnostic utility of immunohistochemical staining for HBME-1, Galectin-3 and CD56 in differentiating FVPTC from its benign mimics, follicular adenoma and adenomatoid nodules, in children. Our specific aim of the project was to define the sensitivity and specificity of the three antibodies in FVPTC. Based on institutional diagnoses, a total of 66 cases were obtained: 32 FVPTC and 34 benign follicular nodules that comprised of 23 follicular adenoma and 11 adenomatoid nodules. Five investigators, who were blinded to the original diagnoses, independently reviewed the slides following pre-determined criteria and semi-quantitatively scoring the immunohistochemical staining. The immunohistochemical staining revealed that a combination of positive HBME-1 and negative CD56 result gave 100% specificity and positive predictive value in distinguishing FVPTC from benign follicular nodules. However, the antibody combination suffered from a lower sensitivity (50%). We used a cutoff of 25% positivity of tumor cells in determining positivity of tumor cells to an antibody. In conclusion, our study found a very high specificity and strong positive predictive value for the combination of HBME-1 and CD56 immunohistochemical stains in distinguishing FVPTC from benign follicular lesions.

Cytomorphology of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features and the Impact of New Nomenclature on Molecular Testing.

The re-naming of noninvasive follicular variant papillary thyroid cancer to the apparently non-malignant, noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) impacts the prevalence of malignancy rates, thereby affecting mutation frequency in papillary thyroid cancer. Preoperative assessment of such nodules could affect management in the future. The original publications following the designation of the new nomenclature have been extensively reviewed. With the adoption of NIFTP terminology, a reduction in the follicular variant of papillary thyroid cancer (FVPTC) prevalence is anticipated, as is a modest reduction of papillary thyroid cancer (PTC) prevalence that would be distributed mainly across indeterminate thyroid nodules. Identifying NIFTP preoperatively remains challenging. RAS mutations are predominant but the presence of BRAF V600E mutation has been observed and could indicate inclusion of the classical PTC. The histological diagnosis of NIFTP to designate low-risk encapsulated follicular variant papillary thyroid cancers (EFVPTCs) would impact malignancy rates, thereby altering the mutation prevalence. The histopathologic criteria have recently been refined with an exclusion of well-formed papillae. The preoperative identification of NIFTP using cytomorphology and gene testing remains challenging.

Molecular characterization of tumors meeting diagnostic criteria for the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

"Follicular variant" papillary thyroid carcinomas (FV-PTC) that do not histologically invade have a miniscule risk of metastasis, and thus been reclassified as a tumor of low malignant potential, the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). There are few molecular studies of this tumor type. We performed gene expression analysis, by RNA sequencing, on a series of FV-PTCs, NIFTPs, and follicular adenomas. A training set comprised tumors from The Cancer Genome Atlas (TCGA) repository (n = 46), digital slides from which were reviewed and classified as invasive ornon-invasive FV-PTC. A validation set comprised in-house NIFTPs, invasive FV-PTCs, and follicular adenomas (n = 26). In the training set, unsupervised clustering separated tumors into three distinct expression subtypes, which associated with invasion and characteristic molecular alterations. Specifically, the "BRAF-like" subtype was enriched in invasive FV-PTCs and tumors with BRAF V600E mutations. The "THADA-like" subtype was enriched in non-invasive tumors and those with rearrangements involving THADA. The "RAS-family-like" subtype included many invasive and non-invasive FV-PTCs and was enriched in tumors with mutations in RAS family genes. In the validation set, nearest centroid analysis classified all invasive FV-PTCs as "BRAF-like" and all follicular adenomas as either "RAS-like" or "THADA-like." NIFTPs were the most molecularly diverse histologic type, with cases classified as "BRAF-like," "THADA-like," and "RAS-family-like." In conclusion, tumors fitting criteria for NIFTP are molecularly diverse, making it difficult to diagnose them with molecular studies, likelyincluding matrial fromcytopathology samples.

Important cytological findings for distinction between follicular variant and conventional papillary thyroid carcinoma, including noninvasive follicular thyroid tumors with papillary-like nuclear features.

We studied cytological specimens of conventional papillary thyroid carcinoma (PTC), follicular variant papillary thyroid carcinoma (FVPTC), and noninvasive follicular thyroid tumor with papillary-like nuclear features (NIFTP) (formerly noninvasive FVPTC) to identify useful cytological parameters for their differentiation. Cytological findings of invasive FVPTC and NIFTP were very similar to each other but differed from those of conventional PTC. Intranuclear cytoplasmic inclusions, true papillary cell clusters, monolayered cell sheets, ropy colloids, multinucleate giant cells, psammoma bodies, and cystic background were the observed characteristic features of conventional PTC. Microfollicular cell clusters and dense globules of colloids were characteristic features of invasive FVPTC and NIFTP. Scoring the eight parameters (intranuclear cytoplasmic inclusions, nuclear grooves, powdery chromatin, true papillary cell clusters, ropy colloids, multinucleate giant cells, psammoma bodies, and cystic background) readily distinguished NIFTP from conventional PTC, but could not distinguish NIFTP from invasive FVPTC. The average total score of NIFTP, invasive FVPTC, and conventional PTC were 2.60 ± 0.55, 2.63 ± 0.62, and 4.57 ± 0.99, respectively. The difference between conventional PTC and NIFTP or invasive FVPTC was statistically significant (p < 0.001, Student's t-test). Individuals with more than three of the identified parameters likely harbor conventional PTC, rather than NIFTP. In this way, 87.5% (112/128) of conventional PTCs could be differentiated from NIFTP, and definitively diagnosed as malignant by cytology.

Diagnostic Value of TROP-2 and CK19 Expression in Papillary Thyroid Carcinoma in Both Surgical and Cytological Specimens.

Papillary thyroid carcinoma (PTC) represents the most common primary malignant thyroid tumor and its diagnosis is dependent on the presence of classic nuclear features that are sometimes seen in some non-neoplastic and benign lesions. Several immunohistochemical markers are used individually or in combination to help in differentiation of PTC from mimickers. The aim of the current study was to assess the diagnostic value of TROP-2 and cytokeratin 19 (CK19) expression in differentiating PTC from other mimickers both singly and in combination. The current study was carried out on 77 surgical specimens (56 PTC and 21 non-neoplastic cases) and 12 cytological specimens (4 THY2, 6 THY4, and 2 THY5). TROP-2 was negative in 81% of non-neoplastic surgical specimens and in 100% of THY2 cytological specimens while it was positive in 71.4% of PTC surgical specimens and 100% of THY4/THY5 cytological specimens. Sensitivity and specificity of TROP-2 positive expression for diagnosis of PTC in surgical specimens reached 71% and 81%, respectively, while it reached 100% for both in cytological specimens. Cytokeratin 19 showed positive expression in 85.7% of non-neoplastic surgical specimens and in 92.9% of PTC surgical specimens. Cytokeratin 19 showed negative expression in 75% of Thy2 cases while it was positive in all studied Thy4 and Thy5 cases. Sensitivity and specificity of CK19 total estimated score for diagnosis of PTC in surgical specimens were 78.6% and 66.7%, respectively, while it reached 100% and 75% in cytological specimens. Positive TROP-2 and CK19 expression in PTC were associated with lymph node metastasis. TROP-2 is a specific rather than sensitive marker while CK19 is a sensitive rather than specific marker in differentiating PTC from other mimickers in surgical specimens. The diagnostic validity of both markers was superior in diagnosis of classic PTC compared with follicular variant PTC. TROP-2 is superior to CK19 in diagnosis of PTC in cytological specimens. Both TROP-2 and CK19 could be used preoperatively in adjunct to hematoxylin and eosin for more confident diagnosis of thyroid cytology and along with radiology as predictors of lymph node metastasis.

CD56, CD57, HBME1, CK19, Galectin-3 and p63 immunohistochemical stains in differentiating diagnosis of thyroid benign/malign lesions and NIFTP.

Detection of thyroid carcinoma has been steadily increased in the past few decades. After the recognition of NIFTP, also gain importance to differentiate benign tumors (follicular adenoma) from follicular patterned variants of papillary thyroid carcinoma (invasive and infiltrative follicular variant papillary thyroid carcinoma), and low-risk lesions of thyroid (NIFTP). Follicular patterned proliferations of thyroid still persists as a battle for pathologists. In this study, we aimed to analyze the most commonly used immunohistochemical stains "HBME1, CK19, Galectin-3", adding the new ones "CD56, CD57, and p63". Study groups were; nodular hyperplasia, follicular adenoma, NIFTP, infiltrative follicular variant PTC, classical variant PTC (CVPTC) and follicular carcinoma. Each group consisted of twenty cases. The sections were stained with CD56, CD57, p63, CK19, HBME1 (Mesotel cell), Galectin-3 antibody. Although the expression of CD56 was high in benign follicular lesions, FC could not be excluded in this group. CD57 was high in malignant follicular group and NIFTP. Interestingly, p63 was found highly expressed in FVPTC, which might be promising to predict invasiveness in follicular group of lesions. CK19, Galectin-3 and HBME1 were found quietly prominent in CVPTC in concordance with the previous reports.

Reanalysis of Lymph node metastasis as predictor of the survival of patients with follicular variant papillary thyroid carcinoma：From SEER database 2004-2014

Reanalysis of Lymph node metastasis as predictor of the survival of patients with follicular variant papillary thyroid carcinoma：From SEER database 2004-2014