To define molecular biology in clinical practice for diagnosis, surgical management, and prognostication of differentiated thyroid cancer.Ovid Medline 2006-2012Manuscripts with clinical correlates.Papillary thyroid carcinomas harbor point mutations of the BRAF and RAS genes or RET/PTC rearrangements, all of which activate the mitogen-activated protein kinase pathway. These mutually exclusive mutations are found in 70% of PTC. BRAF mutation is found in 45% of papillary thyroid cancer and is highly specific. Follicular carcinomas are known to harbor RAS mutation or PAX8/PPARγ rearrangement. These mutations are also mutually exclusive and identified in 70% of follicular carcinomas. Molecular classifiers measure the expression of a large number of genes on a microarray chip providing a substantial negative predictive value pending further validation.1) 20% to 30% of cytologically classified Follicular Neoplasms and Follicular Lesion of Undetermined Significance collectively are malignant on final pathology. Approximately 70% to 80% of thyroid lobectomies performed solely for diagnostic purposes are benign. Molecular alteration testing may reduce the number of unnecessary thyroid procedures, 2) may reduce the number of completion thyroidectomies, and 3) may lead to more individualized operative and postoperative management. Molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ for follicular lesion of undetermined significance and follicular neoplasm improve specificity, whereas molecular classifiers may add negative predictive value to fine needle aspiration diagnosis.

The incidence of thyroid cancer in patients treated operatively for thyroid disease has been historically low (<5%). Previous series have not specifically addressed cancer rates in both euthyroid and hyperthyroid patients. This study examined cancer frequency in patients referred for removal of benign thyroid disease in a multi-institutional series.A total of 2,551 patients underwent thyroidectomy at 3 high-volume institutions. Indeterminate/malignant fine-needle aspiration diagnosis was excluded (n = 1,028). Cancer cases were compared among 1,523 patients with Graves' disease (n = 264), nodular goiter (n = 1,095), and toxic nodular goiter (n = 164). Fisher's exact test, chi-square test, Wilcoxon rank sum, Kruskal-Wallis nonparametric t-tests, and multivariable logistic regression were used.Overall, 238 (15.6%) cancers were recorded: Graves' disease (6.1%), nodular goiter (17.5%), and toxic nodular goiter (18.3%). Cancer rates were significantly different among these groups (p < 0.01) and significantly higher in nodular goiter and toxic nodular goiter vs Graves' disease (p < 0.01); no significant differences in cancer rates were noted among institutions. Overall, 275 patients had thyroiditis (18%). There was a significant association with younger age, male sex, nodular thyroids, and cancer (p < 0.05). Presence of thyroiditis or performance of preoperative fine-needle aspiration was not associated with cancer. Mean cancer size was 1.1 cm (46% >0.5 cm; 39% >1 cm). Most patients underwent total thyroidectomy (80%).These data confirm higher than expected incidental thyroid cancer rates (15.6%) in the largest multi-institutional surgical series to date. Nodular thyroids, males, and young patients were more likely to harbor incidental carcinoma. These data support consideration of initial total thyroidectomy as the preferred approach for patients referred to the surgeon with bilateral nodular disease.

US-guided fine needle aspiration cytology is currently the best diagnostic tool for thyroid nodules. However, it is not sensitive and specific enough for differentiating between benign and malignant follicular tumors. A potentially useful marker for this differentiation is the PAX8-PPARgamma rearrangement, identified in follicular thyroid carcinomas, but not in follicular adenomas or other types of thyroid tumors. The aim of this research was to determine the clinical significance of the PAX8-PPARgamma oncogene in diagnostics follicular thyroid tumors. The study included 62 patients with follicular or Hürthle cell tumors. Gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) from paraffin embedded tissues, and PCR products were checked using the agarose gel electrophoresis. The immunohistochemical analysis was performed on archive paraffin embedded tissues with the monoclonal PPARgamma antibody. The statistical analysis has indicated that neither the expression of PAX8-PPARgamma mRNA, nor the immunohystochemical analysis with the PPARgamma antibody correlate with the patohystological diagnosis. The oncogene, PAX8-PPARgamma has not met the expectations as a reliable tumor marker for differentiation between benign and malignant thyroid tumors, which makes the only reliable histological criteria--capsular and vascular invasion.

Papillary thyroid carcinoma (PTC) is the most common malignant thyroid disease characterized by a high rate of cervical metastases (30-80%), especially due to paratracheal lymph node involvement. "Skip metastasis" are defined as a lateral lymph node metastasis without central lymph node involvement. The aim of this prospective study was to establish the lateral nodal metastasis pattern according to neck level, general occurrence and significance of skip metastasis in PTC. Forty-two previously untreated patients who presented between 2007 and 2011 with concomitant diagnosis of papillary thyroid cancer and metastatic disease of the lateral neck, underwent total thyroidectomy and central and lateral neck dissection. Skip metastases were encountered in 8 (19.5%) patients, four female and four male, with a mean age of 43.3 years. In all patients with lateral skip metastasis, level III nodes were most frequently involved (75%) followed by level IV (50%), while no metastatic disease was found in level IIb. Based on our research, skip metastasis are not uncommon (a lateral lymph node metastasis without central lymph node involvement) and present in approximately 1/5 of PTC patients with cervical lymph node metastasis.

The main issue with the current ultrasonography (US) guidelines is the overestimation of malignant and indeterminate nodules as they do not aid in making decisions to treat patients. To overcome this, new US guidelines for thyroid nodules that have been shown to be better correlated with cytologic results have been proposed. We also suggested specific indications for US-guided fine needle aspiration (FNA) using the new US guidelines.Clinical and pathologic data from 925 patients and 1,419 thyroid nodules were retrospectively collected. All subjects underwent US- and US-guided FNA at Department of Surgery, Wonju Christian Hospital, between March 2010 and July 2011. Sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated for both the current guidelines and the new guidelines.The accuracy, sensitivity, specificity, PPV, and NPV for the current guidelines in predicting malignancy were 24.1%, 99.3%, 62.2%, 25.0%, and 99.8%, respectively. The accuracy, sensitivity, specificity, PPV, and NPV for the new guidelines in predicting malignancy were 66.0%, 96.0%, 86.7%, 47.7%, and 99.4%, respectively.The use of the new US guidelines allow for a more accurate and specific diagnosis and a better treatment plan than the current guidelines. Additionally, the use of the new FNA guidelines may help prevent unnecessary FNAs and promote cost-effective follow-up for patients.

There are still some controversies regarding the cutoff value and the influential factors of thyroglobulin (Tg) concentration in washout fluid from fine-needle aspiration (FNA) biopsy (FNA-Tg) on cervical lymph nodes (LNs) in patients with papillary thyroid cancer (PTC).Our aims were to validate the cutoff value of FNA-Tg in diagnosing malignant LNs on a large scale and to investigate the influential factors that could result in the discrepancy between the final diagnosis and FNA-Tg.We conducted a retrospective cohort study based on hospital records with 528 cases of FNA-Tg measurement from 419 PTC patients.The cutoff value of FNA-Tg was obtained from receiver operating characteristic analysis with final diagnosis. Binary logistic regression analysis was performed to investigate the influential factors.In the final diagnosis, 190 LNs were malignant, and 338 LNs were benign. The median FNA-Tg was 521.2 (3676.8) ng/mL in malignant LNs, and 0.1 (0.2) ng/mL in benign LNs. The optimal cutoff value of FNA-Tg in distinguishing malignant LNs from benign LNs was 1.0 ng/mL (sensitivity, 93.2%; specificity, 95.9%) in all cases. Combining FNA-Tg and FNA cytology showed superior diagnostic power (sensitivity, 98.4%; specificity, 94.4%) when compared with diagnostic strategy using either FNA cytology or FNA-Tg alone. FNA-Tg, serum TSH, and serum Tg were higher in nonthyroidectomized patients than in thyroidectomized patients (P < .001, respectively). FNA-Tg was correlated with serum TSH and Tg levels (P < .001, respectively), and binary logistic regression analysis showed that serum TSH suppression and serum Tg presence independently affected the diagnosis made by FNA-Tg.Our results validated 1.0 ng/mL of FNA-Tg as a cutoff value for diagnosing LN metastasis of PTC and suggested that serum TSH suppression and serum Tg presence should be considered in diagnosing LN malignancy with FNA-Tg in PTC patients.

Previously we identified RTN4IP1 to be differentially expressed in thyroid cancer by sex and the gene is located on chromosome 6q21, a chromosomal region frequently deleted or with loss of heterozygosity in a variety of human malignancies including thyroid cancer.Because the expression and function of this gene is unknown, we sought to characterize its expression in normal, hyperplastic, and benign and malignant thyroid tissue samples and to evaluate its function in cancer cells.RTN4IP1 expression was analyzed in normal and hyperplastic thyroid tissue and benign and malignant thyroid tissue samples. In 3 thyroid cancer cell lines (TPC1 from a papillary thyroid cancer, FTC133 from a follicular thyroid cancer, XTC1 from a Hürthle cell carcinoma), small interfering RNA knockdown of RTN4IP1 was used to determine its role in regulating the hallmarks of malignant cell phenotype (cellular proliferation, migration, apoptosis, invasion, tumor spheroid formation, anchorage independent growth).We found RTN4IP1 mRNA expression was significantly down-regulated in follicular and papillary thyroid cancer as compared with normal, hyperplastic, and benign thyroid neoplasms (P < .05). Moreover, RTN4IP1 mRNA expression was significantly lower in larger papillary thyroid cancers (P < .05). Small interfering RNA knockdown of RTN4IP1 expression increased cellular proliferation (2- to 4-fold) in all 3 of the cell lines tested and increased cellular invasion (1.5- to 3-fold) and migration (2- to 7.5-fold), colony formation (3- to 6-fold), and tumor spheroid formation (P < .05) in 2 of the 3 cell lines tested (FTC-133 and XTC1).This is the first study to characterize the expression and function of RTN4IP1 in cancer. Our results demonstrate RTN4IP1 is down-regulated in thyroid cancer and is associated with larger papillary thyroid cancer and that it regulates malignant cell phenotype. These findings, taken together, suggest that RTN4IP1 has a tumor-suppressive function and may regulate thyroid cancer progression.

Many factors, including relatively young age of thyroid cancer diagnoses and improved survival, have led to increased concerns about the occurrence of second primary malignancies. This paper describes the pattern of occurrence of second primary malignancies in patients who were treated for malignant thyroid neoplasms in an Indian hospital. There were 21 affected patients of the approximately 4500 seen over 25 years. Most of the second primary cancers are solid tumors, and when nonthyroid cancers are the second tumors, ductal carcinoma of the female breast is the most common. Most of these tumors have very short detection intervals (including synchronous occurrences), suggesting that therapy with internal radiation was not contributory to the tumor development. When thyroid malignancies were the second primary cancers, they usually follow radiotherapy to the head and neck region for treatment of the first primary tumor and tend to be of aggressive histologic types than the common well differentiated thyroid carcinomas.

Maternal hypothyroidism has been associated with intellectual impairment in offspring and, subsequently, routine thyroid screening during pregnancy remains controversial. However current literature has reported no benefit of systematic thyroid screening and substitution with levothyroxine of hypothyroid pregnant women on cognitive function in offspring. Recent studies suggest that subclinical hypothyroidism and hyperthyroidism, especially those with TSH >10 mIU/l or <0.1 mIU/l are associated with cardiovascular morbidity and mortality. Genetic markers are being studied in order to clarify the nature of benign or malignant thyroid nodules after fine-needle aspiration whom cytology is indeterminate. They could avoid the need for surgery in many cases.

Purpose of this study is to explore the trade-offs between radio-induced toxicities and second malignant neoplasm (SMN) induction risk of different emerging radiotherapy techniques for Hodgkin's lymphoma (HL) through a comprehensive dosimetric analysis on a representative clinical model.Three different planning target volume (PTVi) scenarios of a female patient with supradiaphragmatic HL were used as models for the purpose of this study. Five treatment radiation techniques were simulated: an anterior-posterior parallel-opposed (AP-PA), a forward intensity modulated (FIMRT), an inverse intensity modulated (IMRT), a Tomotherapy (TOMO), a proton (PRO) technique. A radiation dose of 30 Gy or CGE was prescribed. Dose-volume histograms of PTVs and organs-at-risk (OARs) were calculated and related to available dose-volume constraints. SMN risk for breasts, thyroid, and lungs was estimated through the Organ Equivalent Dose model considering cell repopulation and inhomogeneous organ doses.With similar level of PTVi coverage, IMRT, TOMO and PRO plans generally reduced the OARs' dose and accordingly the related radio-induced toxicities. However, only TOMO and PRO plans were compliant with all constraints in all scenarios. For the IMRT and TOMO plans an increased risk of development of breast, and lung SMN compared with AP-PA and FIMRT techniques was estimated. Only PRO plans seemed to reduce the risk of predicted SMN compared with AP-PA technique.Our model-based study supports the use of advanced RT techniques to successfully spare OARs and to reduce the risk of radio-induced toxicities in HL patients. However, the estimated increase of SMNs' risk inherent to TOMO and IMRT techniques should be carefully considered in the evaluation of a risk-adapted therapeutic strategy.