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.     

A review of the cytomorphological features of NIFTP

Follicular variant of papillary thyroid carcinoma (FVPTC), including encapsulated (E-FVPTC) and infiltrative (I-FVPTC) forms, account for approximately 30% of all PTC. These subtypes demonstrate different biological behavior and molecular profiles when compared to classical PTC. E-FVPTC has low regional recurrence and metastatic potential with a biological behavior similar to that of follicular adenoma. In 2015, a multidisciplinary panel of experts revised the diagnostic terminology for cases of noninvasive E-FVPTC to noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). NIFTP was morphologically defined as a noninvasive follicular patterned neoplasm with nuclear features of PTC and scant nuclear pseudo-inclusions, specifically excluding papillary structures and psammoma bodies. The employment of NIFTP diagnostically has significantly impacted fine needle aspiration (FNA) diagnosis and the associated risk of malignancy employed in reporting thyroid FNA specimens. The emerging literature suggests specific cytomorphologic features more frequently encountered with NIFTP compared to cases of I-FVPTC. This article reviews the cytology literature regarding NIFTP and discusses the significance of this new entity in the practice of thyroid cytopathology.     

TGF-beta/Smad pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma

Poorly circumscribed growth pattern, extra-thyroid extension and high intratumoural lymph vessel density are significantly associated to nodal metastatization in papillary thyroid carcinoma (PTC). It was also shown that transforming growth factor beta (TGF-beta)/Smad-dependent pathway activity is associated with local invasion, nodal metastatization and BRAF-mutated PTCs. We analysed the immunoexpression of TGF-beta, Smad2/Smad3, Smad4 and Smad7 in a series of 42 cases of classic PTC and 33 cases of follicular variant of PTC with known clinico-pathological and follow-up data, as well as BRAF and RAS status. The 75 PTCs were divided into poorly circumscribed (PCPTC) (n?=?53) and well circumscribed (WCPTC) (n?=?22) according to their borders. Nodal metastases were not detected in any WCPTC regardless of the presence of immunoexpression for TGF-beta, Smad2/Smad3, Smad4 and Smad7 and occurrence of BRAF mutation (in 20?% of WCPTCs). Increased cytoplasmatic expression of TGF-beta at the periphery of PCPTC was associated to morphological features of invasiveness, featuring the so-called epithelial-to-mesenchymal transition (EMT), and presence of nodal metastases, as well as to the occurrence of BRAF mutation which did not significantly alter, per se, the frequency of nodal metastases. The nuclear expression of Smad7 was more frequent in WCPTCs than in PCPTCs and was associated with unicentricity and absence of extra-thyroid extension, vascular invasion and nodal metastases. We conclude that nodal metastases are associated to poorly circumscribed, locally invasive PTCs that exhibit low levels of nuclear Smad7 and a peripheral EMT phenotype displaying TGF-beta overexpression, regardless of the occurrence of BRAF mutation.     

Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis

Early lymph node metastasis is common in pancreatic ductal adenocarcinoma (PDAC). The present study has examined the relationship of lymphatic spread to lymph vessel development and the expression of lymphangiogenic cytokines in a series of well-characterized PDACs. The hot spot method revealed the intratumoural and peritumoural lymphatic vessel density (LVD) to be slightly higher in PDACs than in the normal pancreas. The average intratumoural LVD, however, was strikingly decreased. There was no overexpression of vascular endothelial growth factor (VEGF)-C and VEGF-D in PDACs compared with the normal pancreas. LVD and expression of lymphangiogenic cytokines were not related to any of the biological tumour features or to patient survival. Three orthotopic nude mouse PDAC models did not reveal any increase in tumour-associated LVD, despite a high rate of lymph node metastasis. Lymph vessel proliferation was comparable in PDAC and chronic pancreatitis, in both humans and mice. In conclusion, increased lymphangiogenic activity is not required for and does not significantly affect the lymphatic spread of PDAC. The reduced number of human and murine intratumoural lymph vessels indicates that lymphatic metastasis takes place predominantly via peritumoural lymphatic vessels. The weak expression of lymphangiogenic cytokines in neoplastic cells and lymphatic vessel proliferation in peritumoural regions and chronic pancreatitis indicate that inflammation may be the reason for the low rate of lymphangiogenesis.     

Lymphatic vascular density and lymphangiogenesis during tumour progression of carcinoma ex pleomorphic adenoma

AIMS: To assess lymphatic vascular density (LVD) and lymph vessel endothelial proliferation in a series of carcinoma ex pleomorphic adenoma (CXPA) that represents the tumour in the different carcinogenesis phases and tumour progression. METHODS: In 8 cases of early CXPA (intracapsular and minimally invasive tumours), 8 of advanced CXPA (widely invasive tumours) and 10 of pleomorphic adenoma (PA) without malignant transformation, lymphatic vessels and proliferating cells were detected using the antibodies D2-40 and Ki-67 respectively. RESULTS: Comparing early tumours with advanced ones, LVD was not significantly different at the tumour margin. In contrast, regarding intratumoural lymphatics, PA without malignant transformation and early CXPA contained rare, if any, lymph vessels, whereas in widely invasive carcinomas they were more numerous. However, neither intratumoural nor peritumoural LVD were increased in comparison to adjacent normal salivary gland tissue. In no case did dual immunohistochemistry using D2-40 and the cell proliferation marker Ki-67 reveal the existence of proliferating lymphatics. Carcinomatous emboli were found in peritumoural as well as in intratumoural lymphatics only in advanced CXPA without myoepithelial differentiation. CONCLUSION: In CXPA, the lymphatic network is mainly composed of pre-existing lymphatics which are rare in tumours that have not infiltrated outside the confines of the original PA. In the widely invasive CXPA, intratumoural as well as peritumoural lymphatics are a conduit for carcinoma cells, but in carcinomas with myoepithelial differentiation, the neoplastic cells seem to have a lower invasion capacity.     

Peritumoural,but not intratumoural,lymphatic vessel density and invasion correlate with colorectal carcinoma poor-outcome markers

To evaluate whether lymphatic vessel density (LVD) and lymphatic vessel invasion (LVI) are useful markers of worse outcome in colorectal carcinoma and if LVD and LVI correlate to the classical clinical-pathological parameters, we analysed 120 cases of colorectal carcinomas selected from the files of Division of Pathology, Hospital das Clinicas, São Paulo University, Brazil. Assessment of LVD and LVI was performed by immunohistochemical detection of lymphatic vessels, using the monoclonal antibody D2-40. Higher LVD was found in the intratumoural area, when comparing with normal and peritumoural areas (p?p?=?0.037) and liver metastasis (p?=?0.012). Remarkably, LVI was found associated with local invasion (p?=?0.016), nodal metastasis (p?=?0.022) and hepatic metastasis (p?相似文献   

Classical and Follicular Variant Papillary Thyroid Carcinoma: Comparison of Clinical,Ultrasonographical, Cytological,and Histopathological Features in 444 Patients

Follicular variant papillary thyroid carcinoma (FVPTC) is the most common variant of papillary thyroid carcinoma (PTC) after classical PTC (CPTC). In this study, we aimed to compare functional status, ultrasonographical features, cytological results, and histopathological characteristics of patients with CPTC and FVPTC. Preoperative thyroid functions, thyroid autoantibodies, ultrasonographical features, cytology, and histopathology results of 354 (79.9%) CPTC and 90 (20.3%) FVPTC patients were reviewed retrospectively. Sex distribution, mean age, thyroid autoantibody positivity, and thyroid dysfunctions were similar in two groups. Among 320 patients with preoperative ultrasonography (US) findings, a hypoechoic halo was observed more frequently (p = 0.003), and marginal irregularity was observed less commonly (p = 0.024) in FVPTC lesions. In CPTC, rate of malignant cytology (p = 0.001), and in FVPTC, rate of suspicious cytology (p < 0.001) were significantly higher. Histopathologically, mean tumor diameter was markedly higher in FVPTC compared to CPTC (16.89 ± 13.86 vs 10.64 ± 9.70 mm, p < 0.001), while capsular invasion and extrathyroidal spread were significantly lower in patients with FVPTC (p = 0.018 and p = 0.039, respectively). FVPTC tend to have more benign features in US and less malignant results in cytology. Higher tumor size in FVPTC might be explained by the recognition of clinical importance of these lesions after reaching particular sizes due to benign US features.     

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.     

Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients’ age but not with tumour aggressiveness

A high prevalence of the BRAF^V600E somatic mutation was recently reported in several series of papillary thyroid carcinomas (PTC). This mutation appears to be particularly prevalent in PTC with a predominantly papillary architecture. Another BRAF mutation (K601E) was detected in a follicular adenoma and in some cases of the follicular variant of PTC. The few studies on record provided controversial data on the relationship between the occurrence of BRAF mutations and clinicopathologic parameters such as gender, age and tumour staging. In an attempt to clarify such controversies we decided to enlarge our previous series to 315 tumours or tumour-like lesions diagnosed in 280 patients, including a thorough analysis of several clinicopathologic features. The BRAF^V600E mutation was exclusively detected in PTC with a papillary or mixed follicular/papillary architecture both of the conventional type (46%) and of other histotypes, such as microcarcinoma (43%), Warthin-like PTC (75%) and oncocytic variant of PTC (55%). The BRAF^K601E mutation was detected in four of the 54 cases of the follicular variant of PTC (7%). The mean age of patients with conventional PTC harbouring BRAF^V600E (46.7 years) was significantly higher (P<0.0001) than that of patients with conventional PTC without BRAF^V600E (29.5 years). The BRAF (BRAF^V600E) mutated PTC did not exhibit signs of higher aggressiveness (size, vascular invasion, extra-thyroid extension and nodal metastasis) and were in fact less often multicentric than PTC without the mutation.V. Trovisco and P. Soares contributed equally to this workFundação para a Ciência e Tecnologia POCTI/FEDER (POCTI/NSE/48171/2002)     

Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer

Early metastasis to lymph nodes is a frequent complication in human breast cancer. However, the extent to which this depends on lymphangiogenesis or on invasion of existing lymph vessels remains controversial. Although proliferating intratumoural lymphatics that promote nodal metastasis have been demonstrated in experimental breast tumours overexpressing VEGF-C, it has yet to be determined whether the same phenomena occur in spontaneous human breast cancers. To address this important issue, the present study investigated the lymphatics in primary human breast carcinoma (75 cases of invasive ductal and lobular breast cancer) by quantitative immunohistochemical staining for the lymphatic endothelial hyaluronan receptor LYVE-1, the blood vascular marker CD34, and the nuclear proliferation marker pKi67. None of the breast carcinomas was found to contain dividing lymph vessels, even in areas of active haemangiogenesis. Furthermore, the majority of non-dividing lymph vessels were confined to the tumour periphery where their incidence was low and unrelated to tumour size, grade or nodal status; rather, their density was inversely correlated with tumour aggressiveness as assessed by macrophage density (p = 0.009), and blood microvessel density (p = 0.05, Spearman Rank), as well as with distance from the tumour edge. Finally, a proportion of the peritumoural lymphatics contained tumour emboli associated with hyaluronan, indicating a possible role for LYVE-1/hyaluronan interactions in lymphatic invasion or metastasis. These results suggest that naturally occurring breast carcinomas invade and destroy lymph vessels rather than promoting their proliferation; that breast tumour lymphangiogenesis may not always occur at physiological VEGF-C levels; and that nodal metastasis can proceed via pre-existing lymphatics.     

Clinical Utility of KAP-1 Expression in Thyroid Lesions

Although there are evidences of the involvement of KAP-1 in other tumors, data on differentiated thyroid carcinomas (DTC) are still lacking. We aimed to evaluate KAP-1 clinical utility in the diagnosis and prognosis of DTC. We used both visual immunohistochemistry and a semiquantitative analysis to evaluate KAP-1 expression in 230 thyroid carcinomas and 131 noncancerous thyroid nodules. There were 43 follicular carcinomas (FC) and 187 papillary thyroid carcinomas (PTC), including 130 classic (CPTC), 4 tall cells (TCPTC), and 53 follicular variants (FVPTC). Patients were followed up for 53.8?±?41 months. They were classified as free-of-disease (142 cases) or poor outcome (25 cases—10 deaths), according to their serum Tg levels and image evidences. KAP-1 was identified in 78 % PTC, 75 % TCPTC, 74 % FC, 72 % FVPTC, 55 % FA, 44 % hyperplasia, and 11 % normal thyroid tissues. A ROC analysis identified malignant nodules with 69 % sensitivity and 75 % specificity, using a cutoff of 73.19. In addition to distinguishing benign from malignant thyroid tissues (p?<?0.0001), KAP-1 expression differentiated CPTC from nodular hyperplasia (p?<?0.0001), CPTC from FA (p?=?0.0028), FVPTC from hyperplasia (p?=?0.0039), and FC from hyperplasia (p?=?0.0025). Furthermore, KAP-1 was more expressed in larger tumors (>4 cm; p?=?0.0038) and in individuals who presented recurrences/metastases (p?=?0.0130). We suggest that KAP-1 may help diagnose thyroid nodules, characterize follicular-patterned thyroid lesions, and identify individuals with poor prognosis.     

Encapsulated Malignant Follicular Cell-Derived Thyroid Tumors

Encapsulated malignant follicular cell-derived thyroid tumors are subject to considerable controversies. This group includes encapsulated follicular variant of papillary carcinoma (FVPTC) and encapsulated (so-called minimally invasive) follicular carcinoma (EFC). FVPTC usually presents as an encapsulated tumor and less commonly as a partially/nonencapsulated infiltrative neoplasm. The encapsulated form rarely metastasizes to lymph node, whereas infiltrative tumors often harbor nodal metastases. Encapsulated FVPTC have a molecular profile very close to follicular adenomas/carcinomas (high rate of RAS and absence of BRAF mutations). Infiltrative follicular variant has an opposite molecular profile closer to classical papillary thyroid carcinoma than to follicular adenoma/carcinoma (BRAF?>?RAS mutations). Noninvasive encapsulated FVPTC are extremely indolent even if treated with lobectomy without radioactive iodine therapy. Although most EFC are thought to have an excellent outcome, there are cases of EFC that recur and metastasize. EFC with angioinvasion, especially if extensive, have a significant rate of distant recurrence. Encapsulated FVPTC have a molecular profile and a clinical behavior very similar to the follicular adenoma/carcinoma class of tumor. If noninvasive, encapsulated FVPTC should be treated in a very conservative fashion. EFC with angioinvasion, especially if extensive, should not be termed minimally invasive in order to prevent undertreatment of the patient.     

Association between BRAF V600E mutation and regional lymph node metastasis in papillary thyroid carcinoma

Background: BRAF V600E is the most frequent genetic alteration in papillary thyroid carcinoma (PTC); there are ongoing conflicts on its association with regional lymph node metastasis. And we aimed to test this association in a referred sample in a single institute in China. Methods: We analyzed BRAF V600E mutational status in the primary lesion of 150 PTC cases in Peking Union Medical College Hospital (PUMCH) and their corresponding lymph node metastasis (if present and available) using a validated Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) method. Results: Among 150 PTC cases, 121 (80.6%) primary tumors harbored BRAF V600E mutation, 66.9% (81/121) and 79.3% (23/29) had regional lymph node metastasis (LNM) in cases detected with and without BRAF V600E mutation, respectively (P = 0.195). The BRAF V600E mutational status of most of the metastatic lesions was not different to that of their primary foci (73 out of 76 cases, 96.1%, Kappa value = 0.893). The 3 inconsistent cases were all mutation positive for primary tumors and mutation negative for LNM. Conclusion: No association was established between BRAF V600E mutation and regional lymph node metastasis in PTC in Chinese patients.     

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).     

Three-dimensional reconstruction of vessel distribution in benign and malignant lesions of thyroid

In order to better understand the spatial distribution of thyroid vessels, a series of benign and malignant thyroid lesions were studied with three-dimensional (3D) histological stereomicroscopic reconstruction. Cases consisted of normal autoptic thyroids (n=6), colloid goitres (n=6), Basedows disease (n=2), follicular adenoma (FA) (n=4) one of which with Hurthle cells (HC), minimally invasive, well-differentiated follicular carcinoma (FTC) (n=1), well-differentiated FTC with HC (n=1), poorly differentiated FTC (n=13) with extensive angioinvasion, papillary carcinoma (PTC) (n=8) and medullary carcinoma (MTC) (n=1). From each selected nodule, parallel sections were obtained for 3D reconstruction and for histological and immunohistochemical studies. In normal thyroid, large vessels were located at the periphery of the gland with smaller branches present within the thyroid parenchyma that encircled follicles. The same pattern of vascularisation is maintained in lesions showing a follicular architecture as colloid goitre, Basedows disease, FA, well-differentiated FTC and the follicular variant of PTC. Neoplastic lesions, at variance with non-neoplastic lesions, contained rare anastomoses. Poorly differentiated FTC and MTC contained large intratumoural vessels surrounding avascular areas corresponding to solid neoplastic cellular sheets with necrosis. PTC were more vascularised and contained numerous vascular anastomoses. In conclusion, the present data indicate that the vascular distribution is related to the follicular, papillary or solid type of growth. Vascular anastomoses and intratumoural vessels surrounding solid avascular areas are signs of malignancy.     

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.     

Well-Differentiated Thyroid Carcinoma with Concomitant Hashimoto’s Thyroiditis Present with Less Aggressive Clinical Stage and Low Recurrence

Papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC) are the most common differentiated thyroid cancers. Previous studies report that Hashimoto’s thyroiditis (HT) concomitant with PTC is unusual and improves prognosis compared to classical PTC. Few previous studies address FTC concomitant with HT. In this study, we retrospectively analyzed data from one institution and compared clinical presentations and results of treatment of PTC and FTC with and without HT. In addition, studies comparing presentation and long term follow-up prognosis in classical PTC and FTC were conducted. A total of 1,788 PTC patients and 209 FTC patients underwent thyroidectomy with or without lymph node dissection and follow-up at Chang Gung Medical Center in Linkou, Taiwan. All thyroid carcinomas were pathologically classified according to World Health Organization criteria. Histological patterns of PTC were categorized as classical PTC, or PTC with HT. Follicular thyroid carcinoma patients were categorized as FTC or FTC with HT. The dataset contained a total of 1,703 PTC cases categorized as classical PTC, 85 cases of PTC with HT, 201 cases of FTC and eight cases of FTC with HT. Analysis of Classification of Malignant Tumors (TNM) stage revealed a higher percentage of classical PTC in stage IV than HT group (12.03% vs. 4.70%). Mean tumor size of classical PTC was larger than HT group. Although 42.3% of FTC cases presented with distant metastases, no cases of FTC with HT presented with distant metastasis. Cancer-specific mortality was higher in classical PTC group than in PTC with HT. There was 53.2% of FTC without HT assigned recurrent status, and six of them died of thyroid cancer. No cancer mortality or recurrence in HT with FTC. PTC and FTC with HT presented with better clinical stage and better prognosis after same therapeutic modality. In conclusions, both PTC and FTC with HT have less aggressive clinical presentation and better prognosis.     

Pathological findings of the retrospective diagnosis of NIFTP (non-invasive follicular thyroid neoplasm with papillary-like nuclear features) in 84 cases from Turkey and systematic review

AimThe terminology of “noninvasive follicular thyroid neoplasm with papillary-like nuclear features” (NIFTP) was introduced in 2016; and estimated to cause significant effects in the clinical management of thyroid nodules. The aim of our study is to review our cases that were previously diagnosed as non-invasive encapsulated follicular variant PTC (NI/E-FVPTC) which are compatible with NIFTP and to correlate their follow-up.MethodAll thyroidectomy cases evaluated in the last 15 years were screened, and possible NIFTP cases were determined among patients with NI/E-FVPTC and they were re-examined microscopically. Revised histopathological criteria were used for the retrospective diagnosis of NIFTP. Histopathological findings were correlated to follow up information.ResultsTotally 2138 cases had been previously diagnosed with PTC; 481 (22.5%) of them were FVPTC. After microscopic reevaluation of potential NIFTP cases, 84 cases (3.9%) received final diagnosis of NIFTP. 78.6% of NIFTP patients were female (F/M: 66/18); mean age was 49.0, tumor diameter was 22.7 mm and follow-up time was 66.4 months. 17.9% of NIFTP cases were multifocal and 13.1% were bilateral. No recurrence, lymph node involvement or distant metastasis was detected in any of the patients who were followed up. The mean age of the patients who had total thyroidectomy and received RAI was significantly higher than those who did not.ConclusionAlthough conservative treatment of NIFTP with lobectomy is recommended, age of the patients has been continuing to be the most important determinant for the clinicians to decide on total thyroidectomy and RAI ablation therapy at our institution.     

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

BackgroundRigid diagnostic criteria for NIFTP have been recently proposed. The frequency of NIFTP using the new criteria is unknown, and whether abortive papillae are associated with BRAF^V600E mutation has not been studied. The aim of this study is to identify NIFTP by a retrospective review of Follicular Variant of Papillary Thyroid Carcinoma (FVPTC), and to study its incidence as well as the association between immunohistochemical BRAF^V600E expression and abortive papillae in NIFTP.DesignThyroid tumors diagnosed as FVPTC or NIFTP over a period of 18 years (2000–2017) were identified using the laboratory information system. The final pathology reports were reviewed and potential NIFTP were retrieved. The archived slides for these cases were independently reviewed by 2 pathologists. BRAF^V600E (clone: VE1) immunostain was performed on representative tumor blocks. Clinical information including follow-up data was obtained from the electronic medical records.ResultsAmong the 1918 cases with the diagnosis of papillary thyroid carcinoma (PTC), 589 (30.7%) of FVPTC and 136 cases of potential NIFTP were identified. After the review of the archived pathology slides, 29 lesions were morphologically reclassified as NIFTP. Four (13.7%) of these were positive for BRAF^V600E; no association was found between the presence of abortive papillae and BRAF^V600Eexpression (p=0.3). Exclusion of the 4 cases with BRAF^V600Eexpression resulted in 25 lesions of final NIFTP, representing 4.2% of the FVPTC and 1.3% of the PTC. The mean age of the NIFTP patients was 50 years, 87.5% were females. The mean size of the lesions was 1.4 cm (0.1–4.0 cm). Intranuclear pseudoinclusions were not identified, and abortive papillae were identified in 60% of NIFTP. The average follow-up was 70 (28–166) months. There were no adverse events (recurrence or metastasis) in the NIFTP group.ConclusionWhen strictly defined, NIFTP comprises 1.3% of cases perviously classified as PTC. In morphological NIFTP, no correlation is found between the presence of abortive papillae and the BRAF^V600E expression. Intranuclear pseudo-inclusions are not observed in NIFTP. Modification of current morphological criteria to include BRAF^V600E immunohistochemistry test may stratify NIFTP with benign outcome.     

Expression of hypoxia-inducible factor 1 alpha in papillary thyroid carcinoma is associated with desmoplastic stromal reaction and lymph node metastasis

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer, and it early metastasizes into regional lymph nodes. We evaluated immunohistochemically the expression of the hypoxia marker hypoxia-inducible factor 1α (HIF-1α) as well as extracellular matrix protein tenascin C as a marker of stroma remodelling in a cohort of 160 PTCs. Expression of HIF-1α was seen focally accentuated in 100 of the 160 tumours (62.5 %) including 16 cases with equivocal staining (faint staining or only single-cell staining) and 84 cases with unequivocal staining. HIF-1α expression correlated with the degree of desmoplastic stromal reaction as well as with the expression of tenascin C (p?<?0.001, Kruskal–Wallis test, respectively). Moreover, expression of HIF-1α was significantly associated with the presence of lymph node metastases (p?<?0.001, Mann–Whitney test) as well as signs of invasion, namely, peritumoural and extrathyroidal invasion as well as angioinvasion (p?=?0.024, p?<?0.001, p?=?0.017, Mann–Whitney test, respectively). Additionally, PTC with unequivocal HIF-1α nuclear staining was a larger tumour than PTC with negative (?) or equivocal HIF-1α expression (p?<?0.001, Kruskal–Wallis test). Interestingly, the expression of HIF-1α was not significantly associated with BRAF V600E status (p?>?0.05, Mann–Whitney test). Our data show that the expression of HIF-1α is associated with stroma remodelling processes within the tumour and, thus, may play an important role in an invasive behaviour of these tumours independent of BRAF mutation status.