Cases Of Follicular Variant Of Papillary Thyroid Carcinoma Research Articles

High risk of malignancy in cases with atypia of undetermined significance on fine needle aspiration of thyroid nodules even after exclusion of NIFTP.

Fine needle aspiration cytopathology (FNAC) is the most reliable tool for evaluating thyroid nodules. However, diagnosing Bethesda category III, atypia/follicular lesion of undetermined significance (AUS/FLUS), is a major limitation. The aim of this study was to evaluate the risk of malignancy (RoM) in AUS/FLUS nodules. A systematic review was also carried out analyzing the largest series. Totally 1750 cases (9%) diagnosed with AUS/FLUS were evaluated retrospectively out of 19 392 cases within last 13 years. All patients undergoing surgery for AUS/FLUS were included into the study. Histopathology results were correlated; the impact of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) diagnosis on RoM is evaluated. Of the 280 patients (16%) undergoing surgery, neoplasia were detected in 177 (RoN:63.2%) and malignancy in 119 (RoM:42.5%) of these neoplasia. Follicular variant of papillary thyroid carcinoma (FVPTC) was the commonest malignancy (55.5%). Additional 58 (20.7%) nodules were neoplastic, of which 26 (9.3%) were encapsulated follicular tumors with unknown malignancy potential (FT-UMP) and 32 (11.4%) were follicular adenomas. The remaining 103 patients (36.8%) had non-neoplastic nodules. After reevaluation of the encapsulated FVPTC cases, 20 of them were NIFTP and RoM dropped to 35.4% with a relative decrease of 16.7% and an absolute decrease of 7.1%. In our series, 42.5% of nodules with AUS/FLUS were malignant; 63.2% of them were neoplastic. The RoM and RoN for AUS/FLUS nodules are still much higher than the revised expected RoM of international guidelines even after NIFTP cases excluded. Therefore, current recommendations should be reevaluated periodically in view of detailed clinicopathologic studies.

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: Epidemiology and Long-Term Outcomes in a Strictly Defined Cohort.

Background: A subset of encapsulated/circumscribed follicular variant of papillary thyroid carcinoma (FVPTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in 2016 to reduce overtreatment of a low-risk tumor. Study objectives were to describe the epidemiology and long-term outcomes of NIFTP in a high-volume, urban, tertiary referral center. Methods: Among patients enrolled in the Boston Medical Center (BMC) Thyroid Cancer Registry, 110 cases of FVPTC underwent index thyroid surgery at BMC between 2000 and 2016. Historically, BMC pathologists assess all malignant nodules using sections ≤0.3 cm with evaluation of the entire nodule and capsule. After review of pathology reports to identify potential NIFTPs, slides were rereviewed using criteria established by the NIFTP Working Group in 2016 and 2018. We evaluated interobserver reliability using Cohen's Kappa coefficient. Results: Among 110 FVPTCs, 15 (13%) met NIFTP criteria; 11 women and 4 men, age range 31-64 (mean 47.5) years. Mean tumor diameter was 1.7 cm (compared with 2.2 cm for FVPTC). Among NIFTP cases, there were no lymph node metastases, distant metastases, or tumor recurrences. All NIFTP cases were American Thyroid Association (ATA) low risk compared with only 68% of FVPTC (p = 0.011). Among FVPTCs, 14% had positive lymph nodes at index operation. Four patients (4%) had distant metastases. Mean follow-up time was 46 and 69 months for FVPTC and NIFTP, respectively. Among FVPTCs with an excellent response to therapy (2015 ATA guidelines), there were no recurrences. Just over half (n = 8) of patients with NIFTP received postoperative radioactive iodine (RAI) therapy. Concordance between pathologists was high for ruling out NIFTP (75%), but only 36% for ruling in NIFTP. Overall, for NIFTP designation, Cohen's Kappa was 0.39, which is considered fair. Conclusions: Although this is a relatively small cohort, all NIFTP specimens underwent updated pathology review consistent with current guidelines; mean follow-up was nearly 6 years. NIFTP represents a small fraction of the total papillary neoplasia diagnosed at this tertiary referral center (2.3%). None of the NIFTP cohort experienced an adverse oncologic event, and there were no regional or distant metastases. Over 50% of patients with NIFTP received RAI. Thus, the NIFTP reclassification may substantially reduce the number of patients who require adjuvant therapies, such as completion surgery or RAI.

Significance of Insulin-Like Growth Factor II Mrna-Binding Protein 3 (IMP3) Expression in Selected Thyroid Lesions

Background: Differentiation of benign from malignant follicular thyroid lesions remains difficult and the ability of molecular markers to differentiate between them still unclear. The aim of this study was to evaluate the usefulness of IMP3 expression to distinguish benign from malignant thyroid lesions. Methods: This is a retrospective study upon selected 57 thyroid lesions designated as; 7 cases of Hashimoto thyroiditis (HT), 10 cases of hyperplastic nodules (HN), 15 cases of follicular thyroid adenoma (FTA), 13 cases of conventional papillary thyroid carcinoma (PTC), 6 cases of follicular variant of papillary thyroid carcinoma (FV-PTC), and 6 cases of follicular thyroid carcinoma (FTC). Immunohistochemistry was applied on formalin-fixed, paraffin-embeded tissue blocks using IMP3. clinicopathological data were reviewed from patients' pathological reports and correlated with IMP3 expression. Results: IMP3 positivity was seen in1/7 cases (14.3%) of HT, 2/10 cases (20%) of HN, 4/15 cases (26.7%) of FTA, 12/13 cases of PTC, and in all (100%) FV-PTC & FTC cases. IMP3 staining was significantly increased from normal thyroid tissue up to malignant tumors (P<0.01). IMP3 showed 96% sensitivity and 78.1% specificity for malignant tumors. IMP3 expression was positively correlated with grade and tumor size in malignant cases (P<0.05). No significant correlation was found in IMP3 expression with patient age, sex, capsular invasion, lymphatic/vascular invasion, lymph node metastasis, distant metastasis and TNM stage. Conclusions: IMP3 is a potential diagnostic marker for thyroid cancer and can be a promising marker for distinguishing benign from malignant follicular patterned thyroid lesions.

Sonographic features of follicular variant of papillary thyroid carcinoma (FV-PTC) and diagnostic performance of the 2017 ACR TI-RADS in FV-PTC.

To find the sonographic features of follicular variant of papillary thyroid carcinoma (FV-PTC) and evaluate the diagnostic performance of 2017 ACR TI-RADS in FV-PTC. From June 2017 to June 2019, 104 FV-PTC patients (106 nodules) and 337 classic papillary thyroid carcinoma (C-PTC) patients (343 nodules) with both sonograms and pathologic results were included. Sonographic features of FV-PTC and C-PTC were evaluated and compared, and 2017 ACR TI-RADS scores and levels were calculated. Pathologically, the incidence of Hashimoto's thyroiditis and extrathyroidal extension was higher in the FV-PTC group. Most of both the FV-PTC and C-PTC groups were diagnosed as PTC or suspicious PTC by fine-needle aspiration biopsy (FNAB). FV-PTC tended to be isoechoic, while most nodules of C-PTC were hypoechoic or very hypoechoic. Compared with C-PTC, FV-PTC had lower percentages of a taller-than-wide shape (11.3% vs. 46.6%) and lobulated or irregular margin (33.0% vs. 61.8%), and a higher percentage of extrathyroidal extension (20.8% vs. 8.2%). FV-PTC featured macrocalcifications, whereas punctate echogenic foci were more frequently seen in the C-PTC group. Other characteristic US appearances of FV-PTC included uneven hypoechoic halo and peripheral vascularity. The mean TI-RADS score of FV-PTC cases was lower in the FV-PTC group, 11.3%, 44.3%, and 42.5% of which were categorized as TI-RADS 3, 4, and 5, respectively. FV-PTC features isoechoic appearance, macrocalcifications, uneven hypoechoic halo, and peripheral vascularity on US, with lower incidences of microcalcifications and taller-than-wide shape, and tends to have lower TI-RADS scores and levels. For the nodules categorized as TI-RADS 3 or 4, the FNAB criteria should be broaden when these nodules have FV-PTC US features.

The presence of multinucleated giant cells: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features vs the follicular variant of papillary thyroid carcinoma.

Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is a newly described entity with an indolent clinical course as compared to the follicular variant of papillary thyroid carcinoma (FVPTC). As the cytologic features of NIFTP overlap those of the FVPTC, distinction between the two on FNA cytology poses diagnostic difficulties. This study analyzes the presence of multinucleated giant cells (MGCs). Twenty histologically confirmed NIFTP cases and 17 FVPTC cases each with a prior FNA and performed over a 2-year period were reviewed, the cytologic diagnoses compared and the number of MGCs counted. Of the 20 NIFTP cases, 55% were diagnoses as FLUS on FNA, 25% as FN/SFN and 10% as SPTC. Of the 17 FVPTC cases, 12% were diagnosed as FLUS, 53% as FN/SFN and 35% as SPTC. Fifteen (88%) FVTPC cases contained MGCs, whereas none of the 20 NIFTP cases contained MGCs. The presence or absence of MGCs may serve as an additional finding to differentiate NIFTP cases from FVTPC cases.

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.

Identification of distinct cytomorphologic features in the diagnosis of NIFTP at the time of preoperative FNA: Implications for patient management.

A major reclassification occurred with the redesignation of noninvasive encapsulated follicular variant of papillary thyroid carcinoma as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its indolent nature. The aim of this study was to determine whether distinct cytomorphologic features could be identified on preoperative fine-needle aspiration (FNA) when NIFTP cases were compared with invasive follicular variant of papillary thyroid carcinoma (FVPTC) subtypes. Thyroid resection cases with the diagnosis of FVPTC from 2012 to 2016 were reclassified as NIFTP, invasive encapsulated follicular variant of papillary thyroid carcinoma (IEFVPTC), and invasive FVPTC subtypes. Corresponding FNA specimens were retrieved and retrospectively reviewed. A univariate analysis using Fisher's exact test was performed to determine any differences in the frequencies of various cytomorphologic features among NIFTP, IEFVPTC, and FVPTC cases. A multivariate analysis was performed to identify any independent salient features that would be helpful in differentiating NIFTP from its invasive counterparts. The study population consisted of 93 cases, including 51 cases of NIFTP, 21 cases of IEFVPTC, and 21 cases of infiltrative FVPTC. Demographics such as age, sex, and tumor size were comparable across the 3 groups. A predominantly microfollicular pattern, an absence of nuclear pseudo-inclusions, and less frequent nuclear elongations and grooves were significantly more likely to be associated with NIFTP versus its invasive counterparts. The absence of nuclear pseudo-inclusions and the presence of a microfollicular pattern were the only independent predictors of a NIFTP diagnosis. This study demonstrates that NIFTP cases have distinguishing cytomorphologic characteristics in comparison with invasive FVPTC cases. Therefore, a preoperative cytologic evaluation provides clues that can aid in the distinction between NIFTP and its invasive counterparts. Cancer Cytopathol 2017;125:865-75. © 2017 American Cancer Society.

Follicular Variant of Papillary Thyroid Carcinoma on the Basis of His-topathological and Immunohistochemical Diagnosis

A significant increase in incidence of papillary thyroid carcinoma (PTC) has been noticed in recent decades worldwide. This is due to advances in medical surveillance, increased use of ancillary tests, and a minor component due to over diagnosis of PTC. Follicular variant of papillary thyroid carcinoma (FVPTC) is the second most common variant of PTC and comprises about 23-41%. It is difficult to diagnose histologically when the distinctive nuclear features are either not well developed or present focally within the lesion. Several immunohistochemical markers (CD56, HMCK, GAL3, HBME-1 and CK19) either alone or combined in panels can be used to improve diagnostic accuracy. This study was aimed to differentiate FVPTC from other follicular patterned lesion of thyroid by histopathology and immunohistochemistry (IHC). A total of 50 histologically diagnosed cases of thyroid neoplasm were studied. The neoplastic cases included 40 cases of follicular variant papillary carcinoma (FVPC), 04 classic papillary carcinoma (PTC), 04 follicular carcinoma and 02 follicular adenoma. All cases were evaluated by IHC for the expression of CD56 and CK19 antibody. In case of FVPTC (n=40), 21 cases (52.5%) were CK19 positive and CD56 negative as expected. Both markers were found positive in 06 (15%) cases and CD56+ alone was found positive in 11 (27.5%) cases of FVPTC, and a finding that goes against the diagnosis of FVPTC. The histopathological slides of these cases were reviewed and findings were recorded. All cases (n=4) of classic PTC were CK19 positive and 03 (75%) cases were found CD56 negative. Diagnoses of thyroid follicular lesions are primarily based on histological and cytomorphological criteria. However, there was a subset of follicular patterned tumors like FVPTC which lack unequivocal features of malignancy. Immunohistochemistry can improve diagnostic accuracy but needs additional studies for controversial cases. It may be considered these lesions as differentiated tumor of uncertain malignant potential (WDT-UMP) to avoid the using term carcinoma. Additional studies are needed for establishing more precise morphologic criteria and for identifying useful markers for differentiating benign from borderline or malignant thyroid lesions.

Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Accounts for More Than Half of "Carcinomas" Harboring RAS Mutations.

Molecular testing of thyroid nodules is increasingly being utilized to guide clinical management decisions. RAS mutations are the most frequent mutations detected in the context of an indeterminate fine-needle aspiration (FNA) diagnosis. The term "noninvasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) was recently introduced to promote conservative management of tumors previously classified as noninvasive follicular variant of papillary thyroid carcinoma (FVPTC). This change in terminology was based on the indolent clinical behavior of these tumors and their molecular profile, which includes frequent RAS mutations. The aim of this study was to determine the percentage of RAS-mutant "carcinomas" that would now be classified as NIFTPs. A search was performed for cases with known activating RAS mutations in a database of 199 thyroid carcinomas that underwent molecular characterization as part of Profile:Oncopanel between July 2013 and July 2015. Cases of FVPTC were re-reviewed to identify tumors that now would be categorized as NIFTP. Preceding FNA diagnoses were recorded, and cases with an indeterminate FNA result (defined as a diagnosis of atypia/follicular lesion of undetermined significance, suspicious for follicular neoplasm, or suspicious for malignancy) were identified. A total of 27 RAS-mutant thyroid tumors were identified. Fifteen (56%) cases had an NRAS mutation, nine (33%) had an HRAS mutation, and three (11%) had a KRAS mutation. Twenty-four (89%) cases had a preceding FNA, 19 (79%) of which had an indeterminate FNA diagnosis. The surgical resection specimen demonstrated FVPTC in 20 (74%) cases, classical type PTC in two (7%), solid variant of PTC in one (4%), and follicular thyroid carcinoma in four (15%). Of the 20 FVPTCs, 16 (80%) would now be classified as NIFTP. NIFTPs accounted for 59% of RAS-mutant carcinomas overall and 63% of RAS-mutant carcinomas with a prior indeterminate FNA diagnosis. NIFTPs accounted for more than half of RAS-mutant "carcinomas" in this cohort. In cases where clinical and sonographic data support a low-risk phenotype, these results suggest that a lobectomy should be considered as the initial surgical approach for a nodule with an indeterminate FNA diagnosis and a RAS mutation.

Mutational Analysis in Pediatric Thyroid Cancer and Correlations with Age, Ethnicity, and Clinical Presentation.

Background: Well-differentiated thyroid cancer (WDTC) incidence in pediatrics is rising, most being papillary thyroid carcinoma (PTC). The objective of the study was to assess the prevalence of different mutations in pediatric WDTC and correlate the genotype with the clinical phenotype.Methods: This is a single-center retrospective study. Thyroid tissue blocks from 42 consecutive pediatric WDTC patients who underwent thyroidectomy between 2001 and 2013 were analyzed at Quest Diagnostics for BRAFV600E, RAS mutations (N,K,H), and RET/PTC and PAX8/PPARγ rearrangements, using validated molecular methods. Thyroid carcinomas included PTC, follicular thyroid carcinoma (FTC), and follicular variant of PTC (FVPTC).Results: Thirty-nine samples (29 females) were genotyped. The mean age at diagnosis was 14.7 years (range 7.9–18.4 years), and most were Hispanic (56.4%) or Caucasian (35.9%). The mean follow-up period was 2.9 years. Mutations were noted in 21/39 (53.8%), with both BRAFV600E (n = 9), and RET/PTC (n = 6) detected only in PTC. Mutations were detected in 2/5 FTC (PAX8/PPARγ and NRAS) and 3/6 FVPTC cases (PAX8/PPARγ). Of 28 PTC patients, 57.1% had mutations: 32.1% with BRAFV600E, 21.4% with RET/PTC, and 3.6% with NRAS. Of patients with BRAFV600E, 77.8% were Hispanic and 88.9% were >15 years, while all RET/PTC-positive patients were ≤15 years (p = 0.003). Tumor size, lymph node involvement, and distant metastasis at diagnosis (or soon after 131I ablation) did not vary significantly based on the mutation.Conclusions: BRAFV600E was the most common mutation, especially in older and Hispanic adolescents. A larger, ethnically diverse pediatric cohort followed long term will enable the genotypic variability, clinical presentation, and response to therapy to be better assessed.

Follicular Variant of Papillary Thyroid Carcinoma is a Unique Clinical Entity: A Population-Based Study of 10,740 Cases

Follicular variant of papillary thyroid carcinoma (FV-PTC) has been increasingly diagnosed in recent years. However, little is known about its clinical behavior. The purpose of this study was to determine the disease characteristics of FV-PTC, and to compare it with classical papillary thyroid carcinoma (C-PTC) and follicular thyroid carcinoma (FTC). All cases of C-PTC, FV-PTC, and FTC larger than 1 cm in the Surveillance, Epidemiology and End Results (SEER) Cancer Database from 1988 to 2007 were identified. Tumor behavior and patient survival were compared among these three groups. Different risk factors for disease-specific mortality in each group were evaluated by multivariate analysis. More than 36,000 surgical cases were identified, including 21,796 C-PTCs, 10,740 FV-PTCs, and 3958 FTCs. Extrathyroidal extension and lymph-node metastases were more common in FV-PTC than in FTC, but significantly less common than in C-PTC (p<0.0001). Distant metastasis rates were present in 2% of patients with FV-PTC, in 1% with C-PTC, and in 4% with FTC (p<0.0001). The 10-year disease-specific survival for patients with FV-PTC was 98%, similar to C-PTC (97%) but better than FTC (94%, p<0.0001). Being over the age of 45 years remained a strong risk factor for disease-specific mortality in both FV-PTC and C-PTC, while the presence of extrathyroidal extension and distant metastases were stronger predictors of disease-specific mortality in FV-PTC than in C-PTC. FV-PTC is a common variant of PTC. Its clinical behavior is unique and represents an intermediate entity with clinical features that are between C-PTC and FTC. Interestingly, despite the variations in clinical behavior, the long-term outcome of these patients remains excellent and similar to C-PTC.

A Noninvasive Encapsulated Macrofollicular Variant of Papillary Thyroid Carcinoma Presenting with Gross Lymph Node Metastasis: A Case Report and Literature Review

Dear Editor:The follicular variant of papillary thyroid carcinoma (FV-PTC) without vascular or capsular invasion is considered tohave virtually no metastatic potential or recurrence risk (1).The macrofollicular variant of papillary thyroid carcinoma(MFV-PTC) is a very rare variant of FV-PTC the behavior ofwhich appears to be similar to FV-PTC (2). However, morerecently, this phenomenon has been challenged by reports ofsystemic metastases and recurrent and fatal cases (3). We re-port a case of encapsulated noninvasive MFV-PTC that pre-sented with gross lymph node metastases, and briefly reviewthe literature. A right thyroid nodule was incidentally foundby a computed tomography scan in an 80-year-old male.Subsequently, a 3.7cm·3.6cm·3.3cm heterogeneous iso- tohyperechogenic thyroid nodule in the right lobe and a2.2cm·2cm·1.3cm right jugular lymph node, both withcalcifications, were detected by ultrasonography. Fine-needleaspiration biopsy of both lesions was performed under ultra-sonography guidance and showed malignant cells consistentwith PTC. The patient underwent a total thyroidectomy withcentral and right (levels 3–4) lymph node dissection. Thethyroidectomy specimen revealed a 3.7cm·3.2cm·2.9cmencapsulated white solid nodule in the right lobe (Fig. 1),which was entirely submitted for histological evaluation. Onhistology, the nodule was completely surrounded by a thickand focally calcified capsule, without evidence of vascular orcapsular invasion. The nodule was predominantly macro-follicular, with minor areas composed of smaller follicles. Thecells lining the macrofollicles were often attenuated withoutsignificant nuclear atypia (Fig. 1). In contrast, the cells liningthe smaller follicles were more cuboidal and had the typicalnuclear features of PTC (Fig. 1). Numerous intratumoral cal-cifications and psammoma bodies were observed (Fig. 1).Insular/solid growth, necrosis, or mitotic activity was notobserved. Two lymph node metastases were found. Thelargest one (2.4cm) was composed predominantly ofmacrofollicles, akin to the primary tumor (Fig. 1). Im-munohistochemistry was supportive of malignancy, withthe tumor cells being diffusely positive for galectin-3, andfocallypositiveforHBME-1(HectorBattiforamesothelin-1)inthe non-macrofollicular areas only. The proliferative index(Ki-67) in the primary tumor and in the larger metastasis wasvery low ( 50%) was composed ofmacrofollicles (>250lm), corresponding to the arbitrarydefinition of an MFV-PTC (2). Interestingly, that feature wasalso retained in the larger lymph node metastasis, but not inthe smaller one. In the literature, although several cases ofMFV-PTC have presented with lymph node metastasis, mostof these cases were either infiltrative and/or associated withvascular invasion (2). In the largest series of MFV-PTC of 29patients, 6 developed lymph node and 2 developed lungmetastasis (2). The metastases occurred in older patients whohad insular components, extrathyroidal extension, and vas-cular invasion. In our case, although the patient was elderly,no other risk factors were identified. To the best of ourknowledge, there are two other documented cases of encap-sulatedMFV-PTCwithoutcapsularorvascularinvasionwithlymph node and/or systemic metastasis (3). In comparison,we found no well-documented cases of conventional encap-sulated noninvasive FV-PTC with lymph node metastases. Inthe study by Liu et al. (1), the only encapsulated FV-PTC withlymph node metastasis had several foci of lymphovascularinvasion. Moreover, observing that most cases of FV-PTCwith metastatic disease had obvious invasion, Lloyd et al. (4)recommend caution in making a diagnosis of FV-PTC in theabsence of the major histopathologic features or obvious

Investigation of BRAF V600E Mutation in Papillary Thyroid Carcinoma and Tumor-Surrounding Nontumoral Tissues

The aim of this study was to investigate the association between the BRAF V600E mutation incidence and histopathologic prognostic risk factors for papillary thyroid carcinoma (PTC) on the Turkish population. The contribution of BRAF V600E mutation in both tumor and tumor-surrounding nontumoral tissues of 108 patients with PTC was assessed using mutant allele-specific amplification-polymerase chain reaction. The BRAF V600E mutation was found in 52.8% of the tumor tissues, and 7.4% of the tumor-surrounding nontumoral tissues. The BRAF V600E mutation was significantly higher in the tumor tissues of the classic variant of PTC (CVPTC) cases than the follicular variant of PTC cases (p=0.001). The presence of the BRAF V600E mutation was more frequent in women, but this gender difference was not statistically significant. BRAF V600E mutation was more frequent in patients with either one of adenomatous hyperplasia or diffuse hyperplasia in tumor-surrounding nontumoral tissues (p=0.012). There was no significant difference in the BRAF V600E mutation distribution among tumor-surrounding nontumoral tissues of the two PTC variants, but it was more frequent in the CVPTC. Recent data suggest that BRAF V600E is an important marker, especially, for CVPTC. We propose that patients who had subtotal thyroid resection might have an increased risk of recurrence at the residual thyroid tissue if they have BRAF V600E mutation in their tumor-surrounding nontumoral tissues.

Intratumoural lymph vessel density is related to presence of lymph node metastases and separates encapsulated from infiltrative papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) gives frequently rise to nodal metastases via lymphatic vessels while follicular thyroid carcinoma (FTC) metastasises mainly via blood vessels to lung and bones. The follicular variant of PTC (FVPTC) encompasses the infiltrative subtype (I-FVPTC), which shares most of the features of classic PTC (CPTC), and the encapsulated subtype (E-FVPTC), which appears to be related to minimally invasive FTC. In an attempt to contribute to the understanding of the aforementioned differences, we evaluated intratumoural and peritumoural lymph vessels density (LVD), using the immunomarker D2-40 in a series of E-FVPTC, I-FVPTC, and CPTC with known BRAF and RAS status. None of the E-FVPTC cases presented extra-thyroid extension, lymph vessel invasion or nodal metastases, at variance with I-FVPTC and CPTC cases. The BRAF V600E mutation was detected in 8.3% of E-FVPTC, 25.0% of I-FVPTC and in 40.7% of CPTC, while N-RAS Q61R mutation was detected only in 10.3% of FVPTC cases. Only one case of E-FVPTC (8.3%) had intratumoural D2-40-stained vessels in contrast to their presence in 76.5% of the cases of I-FVPTC. Intratumoural LVD determined by D2-40 expression correlated with the occurrence of extra-thyroid extension, lymph vessel invasion and lymph node metastases in PTC cases. At variance with intratumoural LVD, peritumoural LVD was not associated with any clinic-pathological or molecular feature, being similar in E-FVPTC, I-FVPTC and CPTC. Our study highlights the role of intratumoural lymph vessels in PTC nodal metastisation and reinforces the importance of distinguishing E-FVPTC from I-FVPTC regarding invasiveness, metastatic pattern and molecular profile.

Higher Intratumoral Expression of CD1a, Tryptase, and CD68 in a Follicular Variant of Papillary Thyroid Carcinoma Compared to Adenomas: Correlation with Clinical and Pathological Parameters

In a number of human malignancies, the presence of lymphocytic infiltration in or around tumor tissue is commonly considered to be part of the host tumor immune response. An association between thyroid carcinoma and chronic inflammation has been described. This relationship is not fully understood, so we performed a systematic study on a follicular variant of papillary thyroid carcinoma (FVPTC), to evaluate the type and distribution of certain immunological cells and their relationship with prognostic factors. We selected 91 consecutive cases of FVPTC, in which we evaluated the presence of three different immunological cells: dendritic cells (DC), immature CD1a+ and mature DC-Lamp+; mast cells (MC), tryptase+; and macrophages (M), CD68+, in the intratumoral, peritumoral, and extratumoral areas. As a control we analyzed 44 cases of thyroid adenomas (A). In the intratumoral and peritumoral areas, the expression of CD1a, tryptase, and CD68 was significantly higher in FVPTC than in adenomas. Expression of CD1a and tryptase was comparable in the extratumoral compartment, whereas CD68 expression in the extratumoral area was significantly higher in FVPTC than in adenoma (p=0.0015). DC-Lamp expression was not significantly different among the intra-tumor, peri-tumor, and extra-tumor areas of FVPTC or adenoma. It was also very interesting that nonencapsulated FVPTC were more positive to tryptase. We highlight a higher presence of immunological cells in carcinomas than in adenomas. On this basis, it is possible to speculate that these inflammatory elements could be involved in tumor progression and invasion, as appears to be the case for MC and M.

What if Many Follicular Variant Papillary Thyroid Carcinomas are not Malignant? a Review of Follicular Variant Papillary Thyroid Carcinoma and a Proposal for a New Classification

To review the relevant literature concerning follicular variant of papillary thyroid carcinoma (FVPTC) with an emphasis on the heterogeneity of this disorder and to propose a new classification for FVPTC on the basis of molecular diagnostics and apply the classification to a typical case. English-language articles pertaining to FVPTC published between January 1990 and December 2010 were reviewed. FVPTC is particularly vexing. The criteria for diagnosing FVPTC appear to have changed over the years. Pathologists often disagree about the diagnosis of FVPTC. The clinical behavior of these tumors is variable. Molecular diagnostic studies suggest that FVPTC represents a heterogeneous group of disorders rather than a single entity. On the basis of the available data, it is proposed that individual cases of FVPTC be reclassified as papillary thyroid carcinoma, follicular thyroid carcinoma, or follicular adenomas, after appropriate molecular biologic studies have been completed. Long-term follow-up studies to validate this classification are necessary.

Clinical Presentations and Outcomes of Surgical Treatment of Follicular Variant of the Papillary Thyroid Carcinomas

The follicular variant of papillary thyroid carcinoma (FVPTC) presents with biological and morphological features similar to papillary thyroid carcinoma. Pre-operative diagnosis of FVPTC and its clinical course is important in identifying appropriate surgical procedures. This study enrolled 85 patients, 68 females (mean age 41.4+/-13.7 years) and 17 males (mean age 50.1+/-12.3 years) with papillary thyroid carcinomas diagnosed as FVPTC. From the patient database at Chang Gung Medical Center (CGMC), 170 pure papillary thyroid carcinoma cases and 85 with minimally invasive follicular thyroid carcinomas of gender- and age-matched patients were randomly selected as control groups. All patients were categorized into high- and low-risk groups according to AMES criteria. Of the three groups, 7.1% (follicular), 11.8% (FVPTC) and 34.1% (pure papillary thyroid carcinoma) of patients presented with lymph node or soft tissue invasion (P=0.0001). Additionally, 29.4, 11.8 and 2.4% of patients with follicular carcinoma, FVPTC and pure papillary thyroid carcinoma, respectively, presented with distant metastases at the time of diagnosis. Of the 85 FVPTC cases, 75 underwent pre-operative fine needle aspiration cytology (FNAC) examination at CGMC. Only 11 cases were diagnosed pre-operatively with papillary thyroid carcinomas. Kaplan-Meier survival curves for these three groups demonstrated that follicular thyroid carcinoma had a prognosis worse than both papillary thyroid carcinomas. Most FVPTC cases were diagnosed as follicular neoplasm via pre-operative FNAC. In this study, FVPTC patients had a high ratio of distant metastases, few lymph node metastases and soft tissue invasion. Aggressive treatment was indicated for the high-risk FVPTC patients.

PAX8-PPARγ Rearrangement Is Frequently Detected in the Follicular Variant of Papillary Thyroid Carcinoma

The clinicopathological characteristics and the molecular features of the follicular variant of papillary thyroid carcinoma (FVPTC) remain controversial. In an attempt to clarify such controversies and to find whether or not FVPTC cases share the molecular features of follicular tumors, we searched for the presence of PAX8-PPARgamma rearrangements, RAS mutations, and RAP-1, RAF-1, and BRAF mutations in a series of 40 FVPTCs as well as in 27 follicular thyroid carcinomas (FTCs) and 12 follicular thyroid adenomas (FTAs). Fluorescence in situ hybridization and RT-PCR were used to detect the PAX8-PPARgamma rearrangement and PCR, single strand confirmational polymorphism, and sequencing for searching the mutations. The frequency of PAX8-PPARgamma rearrangement was similar in FVPTCs (37.5%), FTCs (45.5%), and FTAs (33.3%). The same holds true regarding the frequency and type of RAS mutations: FVPTC, 25.0%; FTC, 22.2%; and FTA, 33.3%. BRAF mutations were only detected in FVPTC (10%); the BRAF mutations in these cases (K601E and G474R) are different from the typical BRAF(V600E) mutation of conventional PTCs. No mutations were detected in RAP-1 and RAF-1. In FVPTCs, the PAX8-PPARgamma rearrangement was significantly associated with multifocality and vascular invasion, whereas the RAS mutations were significantly associated with the large tumor size. There were three cases of FVPTC, three FTCs and one FTA, harboring both PAX8-PPARgamma rearrangement and RAS mutations; patients with such tumors were usually very young. We conclude that a subset of FVPTC shares some of the molecular features of follicular tumors. Further studies are necessary to clarify the putative clinical significance (e.g. association to blood-born metastases) of PAX8-PPARgamma rearrangement, RAS mutations, and BRAF(K601E) in FVPTCs.

Follicular variant of papillary thyroid carcinoma -- a cytological study.

The cytological diagnosis of classical papillary carcinoma is easily established based on the characteristic architectural and nuclear features. However, the follicular variant of papillary thyroid carcinoma(FVPTC) poses a diagnostic challenge. In this study we analysed the cytological features of 14 histopathologically proven cases of FVPTC. We inferred that a combination of architectural features such as follicles and syncytial clusters and nuclear features, viz grooves, pseudoinclusions and enlarged nuclei with fine chromatin, were helpful in establishing the diagnosis. It is hence suggested that based on the combination of the aforesaid features a diagnosis of FVPTC be offered whenever it is possible. This helps in patient management, obviating the need for a second surgical intervention.

Sensitive cytologic criteria for the identification of follicular variant of papillary thyroid carcinoma in fine-needle aspiration biopsy.

The cytologic diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) can be extremely challenging and may be associated with false negative diagnoses. The purpose of this study was to determine the minimal cytologic criteria needed to identify FVPTC. We examined sixty-nine fine-needle aspiration (FNA) cases, processed with Diff-Quik and Papanicolaou stains, that were either diagnostic or suspicious of FVPTC. All cases had histologic confirmation. These cases included 29 FVPTC, 18 classic papillary thyroid carcinoma (PTC), 17 follicular neoplasm (6 adenomas, 10 carcinomas, 1 neoplasm NOS), 2 lymphocytic thyroiditis and 3 nodular goiter. Seven of the most commonly cited cytomorphologic features, including flat syncytial sheets, nuclear enlargement, fine chromatin, nuclear grooves, nuclear pseudoinclusions, and amount of colloid and cytoplasm, were evaluated. A diffuse distribution of fine chromatin, nuclear grooves, and colloid was seen more often in FVPTC than in follicular neoplasm (p<0.01). The combination of flat/syncytial sheets, nuclear enlargement, and fine chromatin was observed in all our cases of FVPTC, and is therefore considered a sensitive marker in detecting FVPTC. Logistic regression analysis revealed colloid to be the only positive predictor in favor of FVPTC over classic PTC.