The p75 neurotrophin receptor is widely expressed in conventional papillary thyroid carcinoma

Papillary thyroid carcinomas (PTCs) are associated with alterations in several proto-oncogenes related with nervous system development and function, such as TrkA and RET, which are commonly rearranged in these carcinomas. The other oncogenic event recently identified in PTC is the BRAF V600E mutation. Because the role of TrkA was not completely elucidated in thyroid cancer ethiopathogenesis, we decided to study the expression of active, phosphorylated TrkA and of its coreceptor p75 neurotrophin receptor (p75 NTR) in a series of 92 PTC (37 lesions of conventional PTC, 28 of follicular variant of PTC [FVPTC], and 27 of other variants of PTC) as well as in 21 samples of normal thyroid and nonneoplastic thyroid lesions used as a controls. We observed neoexpression of p75 NTR in PTC, particularly in conventional PTC and in other variants of PTC displaying a papillary growth pattern, rather than in FVPTC. No immunoexpression of p75 NTR was observed in normal thyroid nor in nonneoplastic thyroid lesions. The cellular localization of p75 NTR immunoexpression was also significantly associated with the growth pattern of PTC, being much more frequently detected in an apical localization in PTC with papillary architecture than in PTC with a follicular or solid growth pattern. This apical localization of p75 NTR was significantly associated with the presence of BRAF V600E. No significant differences were detected between normal thyroid, nonneoplastic lesions, and PTC (or any PTC variant) regarding expression/activation of TrkA, thus suggesting that by itself and in contrast to p75 NTR, TrkA is not altered during PTC development.     

Survey of 548 oncogenic fusion transcripts in thyroid tumors supports the importance of the already established thyroid fusions genes

Neoplasms frequently present structural chromosomal aberrations that can alter the level of expression of a protein or to the expression of an aberrant chimeric protein. In the thyroid, the PAX8‐PPARG fusion is present in the neoplastic lesions that have a follicular architecture—follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FVPTC), and less frequently in follicular thyroid adenoma (FTA), while the presence of RET/PTC fusions are largely restricted to papillary thyroid carcinoma (PTC). The ability to detect fusion genes is relevant for a correct diagnosis and for therapy. We have developed a new fusion gene microarray‐based approach for simultaneous analysis of all known and predicted fusion gene variants. We did a comprehensive screen for 548 known and putative fusion genes in 27 samples of thyroid tumors and three positive controls—one thyroid cancer cell line (TPC‐1) and two PTCs with known CCDC6‐RET (alias RET/PTC1) fusion gene, using this microarray. Within the thyroid tumors tested, only well known, previously reported fusion genes in thyroid oncology were identified. Our results reinforce the pathogenic role played by RET/PTC1, RET/PTC3, and PAX8‐PPARG fusion genes in thyroid tumorigenesis. © 2012 Wiley Periodicals, Inc.     

The triage efficacy of fine needle aspiration biopsy for follicular variant of papillary thyroid carcinoma using the Bethesda reporting guidelines

Diagnosis of follicular variant of papillary thyroid carcinoma (FVPTC) by ultrasound-guided fine-needle aspiration (FNA) is challenging. In this retrospective review, we evaluated triage efficacy (i.e., potential for triggering surgical intervention) in 44 archived FNA biopsies of surgically confirmed FVPTC obtained between December 2006 and December 2008. We compared the original FNA diagnoses with reclassified diagnoses based on 2007 National Cancer Institute (NCI)/Bethesda recommendations, and reviewed FNA cytologic features. Original FNA diagnoses included colloid nodule (7%, 3/44), atypical follicular cells (5%, 2/44), follicular lesion (11%, 5/44), follicular neoplasm (16%, 7/44), suspicious for malignancy/PTC (27%, 12/44), and papillary thyroid carcinoma (34%, 15/44). Reclassified diagnoses included indeterminate (5%, 2/44), colloid nodule (7%, 3/44), atypical cells of undetermined significance [ACUS] (7%, 3/44), Hurthle cell neoplasm (2%, 1/44), follicular neoplasm (7%, 3/44), suspicious for malignancy/PTC (25%, 11/44), and PTC (48%, 21/44). Triage efficacy was 77% (34/44) for original diagnoses versus 82% (36/44) for reclassified FNA diagnoses. We frequently observed cytologic features of PTC, such as nuclear grooves and fine chromatin; conversely, intranuclear inclusions, though present in 77% cases, were scant. Our review findings suggest that lack of characteristic cytologic features of PTC,coexistence with other thyroid lesions, and small tumor size arethe major obstacles to FNA diagnosis of FVPTC. Reclassification of thyroid FNA diagnoses does not significantly improve triage efficacy. Furthermore, FNA diagnoses of follicular neoplasm and suspicious for malignancy are valuable in patients with FVPTC because they trigger triage toward surgical intervention.     

Diffuse (or multinodular) follicular variant of papillary thyroid carcinoma: a clinicopathologic and immunohistochemical analysis of ten cases of an aggressive form of differentiated thyroid carcinoma

In an attempt to advance and improve the characterization of the so-called diffuse follicular variant of papillary thyroid carcinoma (diffuse FVPTC) we studied a series of 59 thyroid carcinomas consecutively treated in a specialized center. The clinicopathologic and some of the immunohistochemical characteristics (uPA-R, Lewis X, Sialyl Lewis X, and MIB-1) of ten cases of FVPTC displaying a multinodular or diffuse pattern of growth, and histologic features similar to those previously described in diffuse FVPTC, were compared with those of common papillary thyroid carcinoma (PTC, 25 cases) and common FVPTC (8 cases). Cases of diffuse FVPTC differed significantly from common PTC and FVPTC in targeting younger patients and in exhibiting a prevalence of multicentricity, extrathyroid extension, nodal metastasis, and vascular invasion. Immunohistochemically, diffuse FVPTC cases were characterized by the overexpression of uPAR and sialyl Lewis X. No differences were observed regarding MIB 1 immunoreactivity. Regardless of the term used to designate the multicentric, invasive form of FVPTC (diffuse or multinodular FVPTC) it is crucial to acknowledge the existence of cases of FVPTC with a guarded prognosis that should be distinguished from the classic, uninodular form of FVPTC.     

TROP‐2 expression in papillary thyroid carcinoma

TROP‐2 is a type I transmembrane glycoprotein which is over‐expressed in various malignancies, and is related to epithelial cell adhesion molecule (EpCAM), also called TROP‐1, gp40, and KSA. In this study, we evaluated TROP‐2 expression in papillary thyroid carcinoma (PTC) and compared it to other thyroid neoplastic and non‐neoplastic lesions. Immunohistochemical (IHC) evaluation for TROP‐2 was performed on 137 thyroid fine needle aspiration (FNA) cell blocks (CB) which included classic PTC (64), follicular variant PTC (FVPTC) (10), anaplastic thyroid carcinoma (AC) (2), medullary carcinoma (MC) (8), follicular neoplasms (FN) (8), Hurthle cell neoplasms (HCN) (9), follicular lesion of uncertain significance (FLUS) (12), and benign thyroid nodule (BTN) (24). IHC for TROP‐2 expression was also performed on 331 BTN and malignant tumor tissue sections in tissue microarray (TMA). Membranous staining in >5% of tumor cells was considered positive. TROP‐2 stained 61 of 64 PTC CB, 7 of 10 FVPTC CB, and 9 of 12 FLUS CB. All other cases were negative for TROP‐2. TROP‐2 showed a sensitivity of 95.31% and specificity of 89% for classic PTC in FNA CB. In TMA samples, TROP‐2 stained 54 of 60 classic PTC cases and hence showed a high sensitivity and specificity. All BTN in CB and TMA were negative. We conclude that TROP‐2 is a highly sensitive and specific IHC marker for identifying classic PTC. TROP‐2 may play an important role in diagnosing classic PTC, especially in equivocal cases. This study also identifies a strong role for TROP‐2 in separating PTC from BTN. Diagn. Cytopathol. 2016;44:26–31. © 2015 Wiley Periodicals, Inc.     

Follicular variant of papillary thyroid carcinoma: genome-wide appraisal of a controversial entity

The majority of thyroid tumors are classified as papillary (papillary thyroid carcinomas; PTCs) or follicular neoplasms (follicular thyroid adenomas and carcinomas; FTA/FTC) based on nuclear features and the cellular growth pattern. However, classification of the follicular variant of papillary thyroid carcinoma (FVPTC) remains an issue of debate. These tumors contain a predominantly follicular growth pattern but display nuclear features and overall clinical behavior consistent with PTC. In this study, we used comparative genomic hybridization (CGH) to compare the global chromosomal aberrations in FVPTC to the PTC of classical variant (classical PTC) and FTA/FTC. In addition, we assessed the presence of peroxisome proliferator-activated receptor-gamma (PPARG) alteration, a genetic event specific to FTA/FTC, using Southern blot and immunohistochemistry analyses. In sharp contrast to the findings in classical PTC (4% of cases), CGH analysis demonstrated that both FVPTC (59% of cases) and FTA/FTC (36% of cases) were commonly characterized by aneuploidy (P = 0.0002). Moreover, the pattern of chromosomal aberrations (gains at chromosome arms 2q, 4q, 5q, 6q, 8q, and 13q and deletions at 1p, 9q, 16q, 17q, 19q, and 22q) in the follicular variant of PTC closely resembled that of FTA/FTC. Aberrations in PPARG were uniquely detected in FVPTC and FTA/FTC. Our findings suggest a stronger relationship between the FVPTC and FTA/FTC than previously appreciated and support further consideration of the current classification of thyroid neoplasms.     

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.     

Molecular genetic study comparing follicular variant versus classic papillary thyroid carcinomas: association of N-ras mutation in codon 61 with follicular variant

Although the follicular variant of papillary thyroid carcinoma (FVPTC) has been classified as a papillary cancer based on nuclear features, its follicular growth pattern and potential for hematogenous spread are more characteristic of follicular carcinoma. To gain insight into the biologic nature of FVPTC, we compared genetic alterations characteristic of papillary and follicular thyroid carcinomas in 24 FVPTCs and 26 classic PTC (CPTCs). In FVPTCs, we observed ras mutation in 6 of 24 cases (25%), BRAF mutation in 1 of 13 cases (7.6%), and ret rearrangement in 5 of 12 cases (41.7%). In CPTCs, we found ras mutation in no case, BRAF mutation in 3 of 10 cases (30%), and ret rearrangement in 5 of 11 cases (45%). One FVPTC exhibited simultaneous ras mutation and ret/PTC1 rearrangement, and one CPTC harbored simultaneous BRAF mutation and ret/PTC3 rearrangement. Based on these findings, we concluded that ras mutation correlates with follicular differentiation of thyroid tumors whereas ret activation is associated with papillary nuclei but not with papillary architecture. ret activation is not exclusive of ras or BRAF mutation, whereas ras and BRAF mutations are mutually exclusive. The implications of these results for follicular and papillary carcinogenesis are discussed.     

Role of cd56 and e-cadherin expression in the differential diagnosis of papillary thyroid carcinoma and suspected follicular-patterned lesions of the thyroid: the prognostic importance of e-cadherin

Introduction: The pathological diagnosis of papillary thyroid carcinoma (PTC) is generally easy on routine sections stained with hematoxylin and eosin (H&E). However, the differentiation of the follicular variant of PTC (FVPTC) from other suspected follicular-patterned lesions of the thyroid is highly difficult. Among these, the lesions for which FVPTC cannot be excluded are classified as well-differentiated tumors of uncertain malignant potential (WDT-UMP). The most common immunohistochemical (IHC) markers used in the differential diagnosis include HBME-1, galectin-3, and CK19. However, none of these markers provide a 100% differential diagnosis. Objective: The present study compared the diagnostic value of CD56 and E-cadherin for the differentiation of FVPTC from the other benign follicular-patterned lesions, with HBME-1, galectin-3, and CK19. Using these markers, the controversial cases within the WDT-UMP group were reclassified. Additionally, the relationship between the reductions in E-cadherin expression with poor prognostic factors was investigated. Materials and methods: The IHC expressions of CD56, E-cadherin, HBME-1, galectin-3, and CK19 were evaluated in 181 thyroid lesions, including 101 PTCs (45 classical variant PTCs and 56 FVPTCs), 20 WDT-UMPs, 20 follicular adenomas (FAs), 20 hyperplastic nodules (HN), and 20 hyperplastic foci of lymphocytic thyroiditis. The results were statistically compared via SPSS. Results: The expressions of all of the markers were statistically significantly different in PTC and follicular-patterned lesions (P<0.05). It was found that the only marker with both sensitivity and specificity above 90% was CD56 negativity (sensitivity 91.1%, specificity 91.7%). The most sensitive and also the most specific double panel was CD56 negativity and galectin-3 positivity (sensitivity 96%, specificity 85%), and the most sensitive and specific triple panel was CD56 negativity, HBME-1 positivity, and galectin-3 positivity (97% and 70%, respectively).     

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.     

Identification of immunohistochemical biomarkers for papillary thyroid carcinoma using gene expression profiling

We report the successful validation of a combined gene expression profiling and tissue microarray approach to papillary thyroid carcinoma (PTC) biomarker identification. Our ultimate goal is the identification of protein biomarkers that can be effectively used in immunocytochemical assays applied to thyroid fine needle aspiration biopsy (FNAB) samples. To that end, we designed our approach to prioritize molecules that were minimally expressed in normal thyroid and highly expressed in PTC. We first generated gene expression profiles from 11 normal thyroid tissue samples and 9 samples of classic PTC. The results were segregated to rank most highly those molecules not expressed in normal thyroid and up-regulated at least 6-fold in PTC. From this list, we chose 2 molecules (P-cadherin and Bax) for immunohistochemical analysis for which commercial antibodies were available. These were compared with 2 other molecules that have been previously studied in thyroid cancer (cytokeratin-19 and galectin-3). For immunohistochemistry, a tissue microarray was generated that contained the following tissues: classic PTC (n = 20), follicular variant of PTC (n = 9), normal thyroid (n = 19), Hashimoto thyroiditis (n = 11), follicular adenoma (n = 15), and follicular carcinoma (n = 14). Immunohistochemical staining was scored and compared with the gene expression profiling. As anticipated, cytokeratin-19 and galectin-3 were highly expressed in PTC and less expressed in other tissues. Bax and P-cadherin were also expressed in PTC, but to a lower level than cytokeratin-19 and galectin-3; however, Bax and P-cadherin demonstrated virtually no staining of normal thyroid, unlike cytokeratin-19 and galectin-3. These results validate our approach for PTC biomarker discovery and identify several candidate biomarkers for further development.     

HBME‐1 and CD15 immunocytochemistry in the follicular variant of thyroid papillary carcinoma

Papillary carcinoma is the most common thyroid malignancy. As the cytological diagnosis of papillary carcinoma is not difficult in patients with the usual type of lesion, fine‐needle aspiration (FNA) cytology is an effective method for preoperative evaluation. However, this modality is often ineffective in identifying the follicular variant of papillary thyroid carcinoma (FVPTC) due to its similarity to other follicular lesions and the incompleteness of typical nuclear features. Therefore, we investigated the expression of immunocytochemical markers of papillary carcinoma in cytological specimens of FVPTC and evaluated their utilities. The immunoreactivity of HBME‐1 and CD15 was investigated using 50 imprint smear cytological specimens obtained from thyroid lesions, including 13 FVPTC. The sensitivity and specificity of HBME‐1 for FVPTC were 92% and 89%, respectively, while those of CD15 were 23% and 100%, respectively. In conclusion, HBME‐1 is a sensitive marker of papillary carcinoma, including both usual type and FVPTC, in cytological specimens. Therefore, using HBME‐1 immunocytochemistry in FNA cytology will lead to reduction of the incidence of false‐negative diagnoses of FVPTC. Although CD15 is apparently inferior in terms of sensitivity for FVPTC, its excellent specificity will support the definitive diagnosis of thyroid malignancies, including FVPTC, after screening with HBME‐1.     

Immunohistochemical markers in the diagnosis of papillary thyroid carcinomas: The promising role of combined immunostaining using HBME-1 and CD56

We aimed to evaluate the expression and diagnostic value of five immunohistochemical markers (HBME-1, Galectin-3, CK19, CD56 and p63) in a very large series of unequivocal papillary thyroid carcinoma (PTC) cases, including both the classic (CPTC) and the follicular variant (FVPTC).     

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.     

Stage-Specific Embryonic Antigen-1 (SSEA-1) Expression in Thyroid Tissues

Stage-specific embryonic antigen-1 (SSEA-1), also known as CD15, is a member of a cluster of differentiation antigens that have been identified in various normal tissues and in different types of cancers including papillary and medullary thyroid carcinoma. SSEA-1 may be expressed in normal stem cells and cancer stem-like cells. To evaluate the potential diagnostic and prognostic utility of SSEA-1 in thyroid tumors, we analyzed the expression of SSEA-1 in normal and neoplastic thyroid tissues by immunohistochemistry (IHC) using a tissue microarray with 158 different tissue cores. To evaluate the potential utility of SSEA-1 as a surface marker, we also assessed the expression of SSEA-1 in thyroid cell lines by flow cytometric analysis. SSEA-1 immunoreactivity was identified in malignant thyroid follicular epithelial cancers but not in the benign thyroid tissues. Anaplastic thyroid (ATC) (80 %) and conventional papillary thyroid carcinoma (PTC) (60.7 %) showed significantly higher percentage of cases that were SSEA-1 immunoreactive than follicular variant of papillary thyroid carcinoma (FVPTC) (20.6 %) and follicular carcinoma (FCA) (32.1 %). Flow cytometric analysis of cultured thyroid cell lines showed that a small subpopulation of ATC and PTC thyroid tumor cells had SSEA-1 immunoreactivity which may represent thyroid cancer stem-like cells. The ATC cells expressed more SSEA-1 immunoreactive cells than the PTC cell lines. Our findings suggest that expression of SSEA-1 immunoreactivity in thyroid neoplasms was associated with more aggressive thyroid carcinomas. SSEA-1 is a marker that detects malignant thyroid neoplasms in formalin-fixed paraffin-embedded thyroid tissue sections and may be a useful marker for thyroid cancer stem-like cells.     

Encapsulated follicular variant of papillary thyroid carcinoma with bone metastases.

Although true follicular thyroid carcinoma is known to metastasize via the bloodstream and give rise to bone and lung metastases, such a pattern of spread is rare in papillary thyroid carcinoma. The follicular variant of papillary thyroid carcinoma (FVPTC) is believed to behave in a clinical manner similar to usual or classical papillary cancer and to follow a similar indolent course. There have been a few reports of "aggressive" FVPTC wherein follicular patterned tumors with nuclear features of papillary carcinoma have metastasized hematogenously; these neoplasms have been diffusely invasive or multicentric in the thyroid. We report five cases of FVPTC, which were encapsulated and simulated grossly and microscopically follicular adenomas. In two of these, the primary was discovered after clinical presentation of bone metastases. In three others, bony metastases (without other nonosseous metastases) arose 7 to 17 years after thyroid lobectomy for lesions initially diagnosed as follicular adenoma In retrospect, these three encapsulated lesions had vascular invasion. We wish to bring attention to these innocuous-appearing lesions, which, although sharing nuclear features of papillary cancer, behave clinically in an unexpectedly malignant fashion.     

A subset of the follicular variant of papillary thyroid carcinoma harbors the PAX8-PPARgamma translocation

The occurrence of the PAX8-PPARgamma fusion gene is thought to be restricted to follicular tumors (adenomas and carcinomas) of the thyroid (FTA and FTC). Using interphase fluorescent in situ hybridization (FISH), together with recombinant tissue-type polymerase chain reaction (RT-PCR) and immunohistochemistry, we detected the PAX8-PPARgamma translocation in 4 of 8 cases of the follicular variant of papillary thyroid carcinoma (FVPTC) exclusively or almost exclusively (>95%) composed of follicles. The 4 tumors with the translocation were larger and apparently more invasive than the remaining tumors, but the series is too small to allow a statistically meaningful comparison of the data. Our findings show that follicular thyroid carcinoma (PTC) may also harbor the PAX8-PPARgamma fusion gene and indicate that a subset of FVPTC shares some molecular features of FTA and FTC.     

Septin 7 immunoexpression in papillary thyroid carcinoma: A preliminary study

Papillary thyroid carcinoma (PTC) is the most common type among thyroid cancers. The diagnosis of PTC may be challenging when follicular variant (FVPTC) of this disease is present due to the resemblance of nuclear properties of the classical type (CVPTC). However, making use of ancillary molecular markers in the diagnosis of PTC may help. In our study, we aimed to evaluate the SEPT7 protein expression in PTC. A total of 55 paraffin block tissue samples comprising encapsulated FVPTC (FVPTC(e), n = 25), and CVPTC (n = 15), and benign hyperfunctioning thyroid nodules (HypN, n = 15) were used in this study. Nuclear, cytoplasmic, and overall (total) SEPT7 protein expression levels were determined by using immunohistochemistry. Nuclear, cytoplasmic, and overall SEPT7 expressions (p = 0.02, p = 0.001, p = 0.002, respectively) were significantly lower in FVPTC(e) tissues when compared to HypN. In CVPTC group, nuclear expression was significantly lower (p = 0.004) while overall and cytoplasmic expressions were not changed (p > 0.05). In HypN group, highest nuclear (mean = 2.73), cytoplasmic (mean = 2.86), and overall (mean = 2.86) expression scores were detected. Significantly lower SEPT7 expression in all expressional categories in FVPTC(e) group may be a sign of different molecular signature in this type of tissue.     

The preeminence of growth pattern and invasiveness and the limited influence of <Emphasis Type="Italic">BRAF</Emphasis> and <Emphasis Type="Italic">RAS</Emphasis> mutations in the occurrence of papillary thyroid carcinoma lymph node metastases

Prognostic factors indicative of papillary thyroid carcinoma (PTC) aggressive behaviour remain incompletely established partially due to the different composition of the series on record regarding the relative proportion of classic PTC (CPTC) and follicular variant PTC (FVPTC) subtypes. Several clinico-morphological features of PTC, together with the occurrence of BRAF mutations, are still not fully accepted as markers of aggressiveness. In the present clinico-pathological study of a series of 75 CPTC and FVPTC cases, we evaluated the relative contribution of the morphological features of the tumours and their BRAF and N-RAS status for the occurrence of nodal metastases. The morphological features most closely related to the occurrence of nodal metastases were extra-thyroid extension and poorly circumscribed growth pattern, in both CPTC and FVPTC. Additional features significantly associated to nodal metastases were multicentricity in the CPTC and vascular invasion in the FVPTC group. BRAF V600E mutation was detected in 29% of tumours, 41% of CPTC and 16% of FVPTC; N-RAS Q61R mutation was detected in 6% of tumours, 3% of CPTC and 10% of FVPTC. BRAF mutation was significantly more frequent in the CPTC group and in females, and it was detected only in patients older than 20 years, suggesting a late tumourigenic effect in the development of PTC. BRAF mutation was not significantly associated to any of the other studied features related to aggressiveness or nodal metastases. These results highlight the importance of infiltrative growth pattern and invasiveness over the presence of BRAF mutation in classic and follicular variant PTC for the development of nodal metastases.