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et al., [Context]: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. [Objective]: This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). [Methods]: This was a retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33-56 y) and median follow-up time of 37 months (interquartile range, 15-82 mo)., [Results]: The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P < .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC > CPTC ≫ FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66-132.26) and 24.61 (12.31-49.21), 34.46 (30.71-38.66), and 5.87 (4.37-7.88), and 24.73 (18.34-33.35) and 1.68 (0.54-5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07-11.11) and 14.96 (95% CI, 3.93-56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. [Conclusion]: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ≫ FVPTC, providing important clinical implications for specific variant-based management of PTC., This work was supported by the US National Institutes of Health (NIH) Grants No. RO1CA113507 and R01CA189224 (to M.X.). In addition, the studies at individual centers were supported as follows: National Science Centre Poland Grants No. N403 194340 and N N401 612440 to A.C. and B.J., respectively, and Milestone Grant No. 267398 to both (Poland); Grants from Queensland Government Smart State Fellowship and Griffith Health Institute to A.K.L. (Australia); Grants No. RD12/0036/0030 FIS-ISCIII, S2011/BMD-2328 TIRONET, and SAF2013-44709-R to P.So. (Spain); grants from Fondazione Cassa di Risparmio di Perugia and Associazione Italiana per la Ricerca sul Cancro (IG 9338) (Italy) and the Beadle Family Foundation (San Antonio, TX) to E.P.; Grant IGA MH CR NT 13901-4 to V.S. and B.B. (the Czech Republic); grants from the New South Wales Cancer Institute to C.J.O. and from Cancer Council of New South Wales to R.C.-B. (Australia); Italian Government-Ministero della Salute Grant No. RF-2011-02350857 to G.T. (Italy); Grant NIH/NIA 5R03AG042334-02 to L.Y. (United States); Grants from the Ministerodella Istruzione Universitaria e Ricerca Scientifica, the AssociazioneItaliana per la Ricerca sul Cancro, the Istituto Toscano Tumori, and the Ministero della Salute to D.V. and R.E (Italy); and Grant No. CB-2011-03-02 from the Korean Foundation for Cancer Research to Y.K.S. and T.Y.K. (South Korea); Research Grants 2012/02902-9 and 2013/03867-5 from The São Paulo State Research Foundation (FAPESP) to J.M.C. (G.O. is a FAPESP scholar and J.M.C. is a Brazilian Research Council investigator (Brazil); AIRC Grant No. IG 10316 to F.B. (Italy); Grant No. SHDC 12014229 from Shanghai Hospital Development Center to H.X. (China); Programa Operacional Regional do Norte (ON.2—O Novo Norte), under the Quadro de Referência Estratégico Nacional, and through the Fundo Europeu de Desenvolvimento Regional to M.S.-S. and P.So.

Context. There is limited data comparing results of fine needle aspiration biopsies (FNABs) to histological diagnosis in children. Design. FNABs were performed in 707 children and cytological results were compared to histology in 165 cases. The usefulness of immunostaining with anti-TPO monoclonal antibodies (MoAb47) on FNAB samples was examined in 54 operated patients. Results. Among unsatisfactory, benign, suspicious, and malignant FNAB, the histological diagnoses were benign in 12/12 (100%), 69/70 (98.5%), 40/50 (80.0%), and 0/33 (0%), respectively. After surgery, malignancy was established in 44/165 (26.6%) cases. The sensitivity, specificity, and positive and negative predictive values were 95.4%, 55.8%, 61.7%, and 95% with standard FNAB; and 100%, 75%, 73.3, and 100% with MoAb47. Among suspicious FNAB, positive MoAb47 staining was a reliable marker for exclusion of malignancy. Conclusion. Benign and malignant FNAB accurately predict histological diagnosis. In suspicious FNAB, MoAb47 immunostaining may be a useful adjunct to standard cytology.

Purpose: To investigate the overall occurrence and relationship of genetic alterations in the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in thyroid tumors and explore the scope of this pathway as a therapeutic target for thyroid cancer. Experimental Design: We examined collectively the major genetic alterations and their relationship in this pathway, including PIK3CA copy number gain and mutation, Ras mutation, and PTEN mutation, in a large series of primary thyroid tumors. Results: Occurrence of any of these genetic alterations was found in 25 of 81 (31%) benign thyroid adenoma (BTA), 47 of 86 (55%) follicular thyroid cancer (FTC), 21 of 86 (24%) papillary thyroid cancer (PTC), and 29 of 50 (58%) anaplastic thyroid cancer (ATC), with FTC and ATC most frequently harboring these genetic alterations. PIK3CA copy gain was associated with increased PIK3CA protein expression. A mutual exclusivity among these genetic alterations was seen in BTA, FTC, and PTC, suggesting an independent role of each of them through the PI3K/Akt pathway in the tumorigenesis of the differentiated thyroid tumors. However, coexistence of these genetic alterations was increasingly seen with progression from differentiated tumor to undifferentiated ATC. Their coexistence with BRAF mutation was also frequent in PTC and ATC. Conclusions: The data provide strong genetic implication that aberrant activation of PI3K/Akt pathway plays an extensive role in thyroid tumorigenesis, particularly in FTC and ATC, and promotes progression of BTA to FTC and to ATC as the genetic alterations of this pathway accumulate. Progression of PTC to ATC may be facilitated by coexistence of PI3K/Akt pathway–related genetic alterations and BRAF mutation. The PI3K/Akt pathway may thus be a major therapeutic target in thyroid cancers.

The role of aberrant tumor suppressor gene methylation in the aggressiveness of papillary thyroid cancer (PTC) has not been documented. By showing promoter methylation-induced gene silencing in PTC-derived cell lines, we first demonstrated the functional consequence of methylation of several recently identified tumor suppressor genes, including those for tissue inhibitor of metalloproteinase-3 (TIMP3), SLC5A8, death-associated protein kinase (DAPK) and retinoic acid receptor b2 (RARb2). We then investigated the role of methylation of these genes in the aggressiveness of PTC by examining the relationship of their aberrant methylation to clinicopathological characteristics and BRAF mutation in 231 primary PTC tumors. Methylation of TIMP3, SLC5A8 and DAPK was significantly associated with several aggressive features of PTC, including extrathyroidal invasion, lymph node metastasis, multifocality and advanced tumor stages. Methylation of these genes was also significantly associated with BRAF mutation in PTC, either individually or collectively in various combinations. Methylation of these genes, either individually or collectively, occurred more frequently in more aggressive classical and tall-cell PTC subtypes than in less aggressive follicularvariant PTC, with the latter known to infrequently harbor BRAF mutation. Several other tumor suppressor genes investigated were not methylated. These results suggest that aberrant methylation and hence silencing of TIMP3, SLC5A8, DAPK and RARb2 ,i n association with BRAF mutation, may be an important step in PTC tumorigenesis and progression. ' 2006 Wiley-Liss, Inc.

Context: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. Objective: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. Design, Setting, and Subjects: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. Main Outcome Measure: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. Results: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3–29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1–14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. Conclusions: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.