Racial disparities of differentiated thyroid carcinoma: clinical behavior, treatments, and long-term outcomes.

BACKGROUND: The incidence of thyroid cancer in black Americans is significantly lower than that in white Americans, and the impact of race on the prognosis of thyroid cancer remains controversial. The purpose of this study was to determine the risk factors for survival in black and white patients and to compare the survival of differentiated thyroid carcinoma subtypes between these two races. We further investigated the association of lymph node and distant metastases with races. METHODS: This is a retrospective analysis using data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. A total of 70,346 cases were included in our study. Patients' demographics and cancer- and treatment-related characteristics were compared between the black and white Americans using chi-square and Fisher's exact tests. For multivariate analysis, Cox proportional hazards regression were used to assess the association between potential risk factors and the survival in black and white patients. RESULT: Black Americans had a worse overall survival than white Americans (HR = 1.127, P = 0.002). While disease-specific survival (DSS) was comparable, the risk factors for DSS were different between white and black Americans. Black Americans had less lymph node metastasis of classical variant papillary thyroid carcinoma (CPTC, OR = 0.476, P < 0.001) and follicular variant papillary thyroid carcinoma (FVPTC, OR = 0.522, P < 0.001), but not follicular thyroid carcinoma (FTC). However, black Americans with FVPTC, but not CPTC or FTC, had a higher potential of distant metastasis (OR = 1.715, P = 0.026). Furthermore, only white patients with tumor > 2 cm and lymph node metastasis benefited from radioactive iodine. CONCLUSIONS: The risk factors for DSS were significantly different in white and black patients. The impact of race should be considered in treatment strategy for thyroid cancer.

Prognostic markers in well differentiated papillary and follicular thyroid cancer (WDTC).

OBJECTIVES: WDTC (papillary and follicular thyroid cancer) make up around 90% of all thyroid tumours. Overall, the prognosis in patients with WDTC is excellent. However, there are small cohorts of patients who experience a more aggressive form of disease which is often associated with certain poor prognostic factors. Identifying these patients at an early stage is imperative for guiding treatment decisions. With recent developments in this area we plan to discuss the current evidence surrounding prognostic markers. METHODS: The literature regarding prognostic factors in WDTC was reviewed using an electronic database Medline - Pubmed. Using the MeSH search engine specific prognostic factors including age, size, grade, lymph node involvement, distant metastasis, extension/invasion, ethnic background, radioactive iodine avidity, and thyroglobulin level and their association with WDTC were evaluated. A broader search of prognostic markers in thyroid cancer was also carried out to avoid missing other pertinent markers. RESULTS: Multiple clinical and pathologic variables have been shown to be poor prognostic factors in WDTC with statistical significance. Extensive extrathyroidal extension and age may be the most important factors when predicting clinical outcomes in WDTC, although the age threshold may be increased from 45 to 55 years in due course. CONCLUSIONS: Management of WDTC has changed considerably over the last two years as reflected in evolving British and American Thyroid Guidelines. In all cases a combined multi-disciplinary approach, with consideration of the available guidelines and stratification systems should be utilised when planning an individualised treatment program to offer the best contemporary care to WDTC patients.

Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation.

BACKGROUND: Mutations in the TERT promoter, ALK rearrangement, and the BRAF V600E mutation are associated with aggressive clinicopathologic features in thyroid cancers. However, little is known about the impact of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of BRAF mutations. METHODS: We performed Sanger sequencing to detect BRAF V600E and TERT promoter mutations and both immunohistochemistry and fluorescence in situ hybridization to identify ALK rearrangement on 243 thyroid cancers. RESULTS: TERT promoter mutations were not present in 192 well-differentiated thyroid carcinomas (WDTC) without distant metastasis or in 9 medullary carcinomas. However, the mutations did occur in 40 % (12/30) of WDTC with distant metastasis, 29 % (2/7) of poorly differentiated carcinomas and 60 % (3/5) of anaplastic carcinomas. ALK rearrangement was not present in all thyroid cancers. The BRAF V600E mutation was more frequently found in WDTC without distant metastasis than in WDTC with distant metastasis (p = 0.007). In the cohort of WDTC with distant metastasis, patients with wild-type BRAF and TERT promoter had a significantly higher response rate after radioiodine therapy (p = 0.024), whereas the BRAF V600E mutation was significantly correlated with progressive disease (p = 0.025). CONCLUSIONS: The TERT promoter mutation is an independent predictor for distant metastasis of WDTC, but ALK testing is not useful for clinical decision-making in Korean patients with a high prevalence of the BRAF V600E mutation. Radioiodine therapy for distant metastasis of WDTC is most effective in patients without BRAF V600E and TERT promoter mutations.

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 BRAF(V600E), 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 BRAF(V600E) (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 BRAF(V600E), 21.4% with RET/PTC, and 3.6% with NRAS. Of patients with BRAF(V600E), 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 (131)I ablation) did not vary significantly based on the mutation. CONCLUSIONS: BRAF(V600E) 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.

TERT promoter mutations in thyroid cancer: a report from a Middle Eastern population.

Telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have recently been described in follicular cell-derived thyroid cancer (TC) in patients from North America and Europe. In this study, we explored whether these findings could be replicated in patients from a different ethnic group. We screened 17 benign thyroid adenomas and 265 TC samples from patients in the Middle East for these mutations by PCR and direct sequencing using DNA isolated from paraffin-embedded tumor tissues. None of the 17 benign adenomas harbored TERT promoter mutations. Of 265 TC, 34 (12.8%) harbored TERT promoter mutations, including 10/153 (6.5%) conventional papillary TC (CPTC), 8/57 (14.0%) follicular variant PTC, 9/30 (30%) tall cell variant PTC, 1/3 (30%) Hurthle cell thyroid cancer (HTC), 1/5 (20%) follicular TC, and 5/13 (38.5%) poorly differentiated TC. C250T mutation was present in only 6/265 (2.3%) cases, while C228T mutation was present in a total of 28/265 (10.6%) cases. These two mutations were mutually exclusive. TERT promoter mutations were significantly more common in older (≥45 years) than younger patients and were associated with larger tumour size, vascular invasion, higher TNM stage (stage III and IV), BRAF(V600E) mutation and persistent/recurrent disease at 6-12 months after initial treatment and at the last follow up. These associations were stronger in non-CPTC. Thus, this study on a large cohort of TC patients from Middle East demonstrates that TERT promoter mutations are relatively common, especially in the non-CPTC, and are associated with more aggressive histopathological features, BRAF(V600E) mutation, and disease persistence/recurrence than the WT TERT.

A Bedside Risk Calculator to Preoperatively Distinguish Follicular Thyroid Carcinoma from Follicular Variant of Papillary Thyroid Carcinoma.

BACKGROUND: Follicular thyroid carcinoma (FTC) and follicular variant of papillary thyroid carcinoma (FV-PTC) are difficult entities to distinguish based on cytology prior to pathologic evaluation of surgical specimens but may have different treatment algorithms. The current study describes trends in rates of FTC versus FV-PTC in the U.S. and develops a risk assessment tool to aid clinicians in predicting final diagnosis and shaping treatment plans. METHODS: Relative rates of FTC and FV-PTC in the surveillance, epidemiology, and end results (SEER) database were evaluated for temporal trends from 1988 to 2011. Using multivariable logistic regression, a simplified scoring system was developed to estimate the risk of FTC versus FV-PTC using patient and tumor characteristics. The National Cancer Data Base was used for model validation. RESULTS AND DISCUSSION: Of 115,091 thyroid cancer cases in the SEER database from 1988 to 2011, 23,980 involved FTC (n = 5056; 21 %) or FV-PTC (n = 18,924; 79 %). In 1988, half of follicular cases were FV-PTC; however, FV-PTC accounted for over 85 % of these lesions by 2010. Increasing age >45 years, male gender, black race, increasing tumor size, and distant metastases were strongly associated with increased risk of FTC, while lymph node disease and extrathyroidal extension were associated with FV-PTC. A bedside risk assessment nomogram using these preoperative variables classified patient risk of FTC from 2 to 70 %. FV-PTC has become the dominant malignancy with follicular cytology, accounting for >85 % of these cases. A simple bedside risk assessment tool can risk stratify patients with follicular lesions and inform patient and clinician discussions and decision making.

Fine needle aspiration of thyroid nodules in the pediatric population: a 12-year cyto-histological correlation experience at North Shore-Long Island Jewish Health System.

BACKGROUND: Diagnostic evaluation of thyroid nodules by FNA is used in the clinical management triage based on the knowledge of the rate of malignancy of each diagnostic category. The Bethesda System for Reporting Thyroid Cytopathology was published in 2007 by the National Cancer Institute (NCI). Using this classification, we studied our institution's experience in the pediatric population calculating the rate of malignancy for each diagnostic category, comparing our findings to our general patient population and that of the literature. METHODS: 13,312 thyroid FNAs were performed at our institution between 1998 and 2010. 282 cases were from patients under 19 years of age. We reviewed and reclassified these cases using the new NCI categories, and pursued cytology-surgical follow-up. RESULTS: Of the 282 FNA cases, 20.92% (59) were classified as unsatisfactory (U), 48.22, % (136) benign (B), 2.12% (6) Atypia of undetermined significance (AUS), 14.18% (40) suspicious for follicular neoplasm (FN), 2.12% (6) suspicious for malignancy (SM) and 12.41% (35) positive for malignancy (P). The U-category was further classified into nondiagnostic (ND) 12.41% (35) and cysts (C) 8.51% (24). Seventy-four children had surgical follow-up. The rates of histologically confirmed malignancy were 10% in U (1/10), 0% in B (0/17), 50% in AUS (2/4), 39% in FN (7/18), 100% in SM (4/4) and 100% in P (24/24) categories respectively. Among the U category, malignancy rate was 0% for the ND category and 25% for the C category. CONCLUSIONS: To our knowledge, this is the first study to apply the NCI categories to the pediatric population. The rate of malignancy in the U category was only seen in the specimens with cystic component. AUS and FN categories had a higher malignancy rate (50 and 39% respectively) as compared with that of the general population (15 and 30% respectively). Given that the rates of malignancy are higher for cysts and AUS, the literature recommendation to "follow-up and repeat" may not apply to the pediatric population. Surgery may be reasonable in these categories instead.

Association of p53 (-16ins-pro) haplotype with the decreased risk of differentiated thyroid carcinoma in Iranian-Azeri patients.

Association of P53 polymorphisms with the increased risk of various cancers has been investigated in numerous studies. However, the results were conflicting and no polymorphism has been determined as a definite risk factor. It is likely that the study of P53 combined genotypes and haplotypes may be more useful than individual polymorphisms. Thus, in this study, we analyzed the associations of intron 3 Ins16bp and exon 4 Arg72Pro polymorphisms, as well as their combined genotypes and haplotypes with the risk of differentiated thyroid carcinoma in Iranian-Azeri patients. This case-control study was performed on 84 Iranian Azeri patients with differentiated thyroid carcinoma and 150 healthy subjects. Intron 3 genotype was determined using PCR products analysis on polyacrylamide gels and AS-PCR was used for genotyping Arg72Pro polymorphism. The javastat online statistics package software and SHEsis program were applied for data analysis. There was no significant difference in genotype frequencies of both two polymorphisms between cases and controls. However, the (-16 ins/-16 ins) (Arg/Pro) genotype combination had a noticeable but not significant association with decreased risk of thyroid cancer development (OR = 0.497 95%CI: 0.209-1.168 P = 0.080) and also the frequency of (-16 ins-Pro) haplotype was significantly higher in controls rather than patients (OR = 0.543 95%CI: 0.326-0.903 P = 0.018). In our study, there was association between (-16 ins-Pro) haplotype with decreased risk of differentiated thyroid carcinoma development in Iranian-Azeri patients.

Thyroid cancer incidence patterns in Sao Paulo, Brazil, and the U.S. SEER program, 1997-2008.

BACKGROUND: Thyroid cancer incidence has risen steadily over the last few decades in most of the developed world, but information on incidence trends in developing countries is limited. Sao Paulo, Brazil, has one of the highest rates of thyroid cancer worldwide, higher than in the United States. We examined thyroid cancer incidence patterns using data from the Sao Paulo Cancer Registry (SPCR) in Brazil and the National Cancer Institute's Surveillance Epidemiology End Results (SEER) program in the United States. METHODS: Data on thyroid cancer cases diagnosed during 1997-2008 were obtained from SPCR (n=15,892) and SEER (n=42,717). Age-adjusted and age-specific rates were calculated by sex and histology and temporal patterns were compared between the two populations. RESULTS: Overall incidence rates increased over time in both populations and were higher in Sao Paulo than in the United States among females (SPCR/SEER incidence rate ratio [IRR]=1.65) and males (IRR=1.23). Papillary was the most common histology in both populations, followed by follicular and medullary carcinomas. Incidence rates by histology were consistently higher in Sao Paulo than in the United States, with the greatest differences for follicular (IRR=2.44) and medullary (IRR=3.29) carcinomas among females. The overall female/male IRR was higher in Sao Paulo (IRR=4.17) than in SEER (IRR=3.10) and did not change over time. Papillary rates rose over time more rapidly in Sao Paulo (annual percentage change=10.3% among females and 9.6% among males) than in the United States (6.9% and 5.7%, respectively). Regardless of sex, rates rose faster among younger people (<50 years) in Sao Paulo, but among older people (≥50 years) in the United States. The papillary to follicular carcinoma ratio rose from <3 to >8 among both Sao Paulo males and females, in contrast to increases from 9 to 12 and from 6 to 7 among U.S.males and females, respectively. CONCLUSIONS: Increased diagnostic activity may be contributing to the notable rise in incidence, mainly for papillary type, in both populations, but it is not likely to be the only reason. Differences in iodine nutrition status between Sao Paulo and the U.S. SEER population might have affected the observed incidence patterns.

Follicular thyroid cancer incidence patterns in the United States, 1980-2009.

BACKGROUND: The increases in thyroid cancer overall and in the predominant papillary type have been well documented, but trends for follicular thyroid cancer, a less common but more aggressive variant, have not been as well characterized. In this study, we determined the incidence patterns for follicular thyroid cancer and compared trends between the follicular and papillary thyroid cancers in the United States. METHODS: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program to examine incidence in the United States during 1980-2009, stratified by demographic and tumor characteristics. Incidence rates (IR) were calculated, relative risks were expressed as incidence rate ratios (IRR), and temporal trends were expressed as percentage changes and plotted. RESULTS: Overall we observed a modest increase in age-adjusted follicular thyroid cancer rates among women (31.89%) and men (35.88%). Rates increased most dramatically for regional stage tumors compared to localized tumors in women, whereas the rates for all tumor sizes rose. These findings reveal increases in more aggressive tumors in women in addition to small and localized tumors. The trends for males were different from those among females. Among males, the largest increase was observed for regional and smaller size tumors. The papillary-to-follicular IRR overall was 7.07 [95% confidence interval 6.91-7.24], which varied from 7.37 among Whites to 3.86 among Blacks (SEER race/ethnicity categories), and increased significantly from 3.98 during 1980-1984 to 9.88 during 2005-2009. CONCLUSION: The different trends for follicular and papillary types of thyroid cancer illustrate that thyroid cancer is a heterogeneous disease. Our results do not support the hypothesis that increasing thyroid cancer rates are largely due to improvements in detection, and suggest the importance of evaluating thyroid cancer types separately in future studies.

Incidence of thyroid malignancy among goitrous thyroid lesions from the Sarawak General Hospital 2000-2004.

INTRODUCTION: Thyroid cancer is the most common among all endocrine malignancies. The worldwide prevalence of goitre in the general population is estimated at 4-7 percent and the incidence of malignancy in goitrous thyroid is about ten percent. It is postulated that goitrous thyroid is a precursor lesion to the development of malignant thyroid diseases. As Sarawak is a state well known for endemic goitre, this study focused on establishing the incidence of thyroid malignancy among goitrous thyroid swellings. METHODS: This study was a hospital-based retrospective study on the archived collection of the surgically-removed thyroid specimens from the Sarawak General Hospital, Malaysia. Cases were grouped into cancer and non-cancer groups. The cancer group included papillary thyroid carcinoma (PTC), PTC follicular variant, follicular carcinoma and anaplastic carcinoma (ANA). RESULTS: A total of 820 thyroid cases which underwent surgical removal in years 2000 to 2004 were collected. Of these, 143 (17.4 percent) were male and 677 (82.6 percent) female. It was observed that the highest prevalence of thyroid swelling cases occurred in the age group 41-60 years while the lowest prevalence occurred in the age group under 21 years, 371 (45.2 percent) vs. 31 (3.8 percent). By ethnicity, the Ibans and Malays were found to have a higher prevalence at 275 (33.5 percent) and 196 (23.9 percent), respectively, while the lowest prevalence was observed in Indians, 11 (1.3 percent). 55 cases (6.7 percent) were found to be cancerous and the rest (93.3 percent) were non-cancerous thyroid swellings. Histologically, the highest incidence of carcinoma was PTC (4.0 percent) and the lowest was ANA (0.2 percent). CONCLUSION: Based on our observations, although goitrous thyroid swelling is quite a common problem in Sarawak, thyroid malignancy is not a major issue. Among thyroid malignancies, PTC is the most common histological type of malignancy.

Rising thyroid cancer incidence in the United States by demographic and tumor characteristics, 1980-2005.

Thyroid cancer incidence has been rising in the United States, and this trend has often been attributed to heightened medical surveillance and the use of improved diagnostics. Thyroid cancer incidence varies by sex and race/ethnicity, and these factors also influence access to and utilization of healthcare. We therefore examined thyroid cancer incidence rates by demographic and tumor characteristics based on 48,403 thyroid cancer patients diagnosed during 1980-2005 from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. The rates varied by histologic type, sex, and race/ethnicity. Papillary carcinoma was the only histologic type for which incidence rates increased consistently among all racial/ethnic groups. Subsequent analyses focused on the 39,706 papillary thyroid cancers diagnosed during this period. Papillary carcinoma rates increased most rapidly among females. Between 1992-1995 and 2003-2005, they increased nearly 100% among White non-Hispanics and Black females but only 20% to 50% among White Hispanics, Asian/Pacific Islanders, and Black males. The increases were most rapid for localized stage and small tumors; however, rates also increased for large tumors and tumors of regional and distant stage. Since 1992-1995, half the overall increase in papillary carcinoma rates was due to increasing rates of very small (2 cm. Among White females, the rate of increase for cancers>5 cm almost equaled that for the smallest cancers. Medical surveillance and more sensitive diagnostic procedures cannot completely explain the observed increases in papillary thyroid cancer rates. Thus, other possible explanations should be explored.

High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors.

CONTEXT: Genetic alterations in the phosphatidylinositol-3-kinase (PI3K)/Akt pathway and their role in thyroid tumor pathogenesis in Chinese people remain undefined. OBJECTIVE: The objective of the study was to examine the major genetic alterations and their relationship in the PI3K/Akt pathway in differentiated thyroid tumors in a Chinese cohort. DESIGN: We used real-time quantitative PCR for the analysis of PIK3CA copy gain and direct DNA sequencing for the detection of PIK3CA, RAS, and PTEN mutations on genomic DNA isolated from 234 thyroid tumors, including 31 follicular thyroid cancer (FTC), 141 papillary thyroid cancer (PTC), and 62 follicular thyroid adenoma (FTA). RESULTS: We found PIK3CA copy gain (defined as four or more copies) in nine of 31 FTC (29%), 20 of 141 PTC (14%), and five of 62 FTA (8%); PIK3CA gene mutations in four of 31 FTC (13%), one of 141 PTC (1%), and none of 62 FTA (0%); Ras mutations in three of 31 FTC (10%) and none of the 141 PTC and 62 FTA; and PTEN mutations in two of 31 FTC (6%) and none of 62 FTA (0%). Collectively, nine of 31 FTC (29%) vs. none of 62 FTA (0%) (P < 0.01) harbored one of the mutations, and when PIK3CA copy gain was included, 16 of 31 FTC (52%) vs. five of 62 FTA (8%) (P < 0.01) harbored any genetic alteration in the PI3K/Akt pathway. Mutual exclusivity was seen among all these PI3K/Akt pathway-related genetic alterations in all thyroid tumors except for two cases that harbored two genetic alterations. CONCLUSION: These data from a Chinese cohort provide further genetic evidence suggesting that dysregulated PI3K/Akt pathway plays a significant role in the pathogenesis of thyroid tumors, particularly FTC.

Selective occurrence of ras mutations in benign and malignant thyroid follicular neoplasms in Taiwan.

Previous studies have demonstrated that point mutations in all three ras genes (H-ras, K-ras, and N-ras) may occur in thyroid neoplasia. However, the overall incidence of ras mutations in thyroid tumors and their frequency in specific histologic types varies widely in different series. Many earlier studies have chosen allele-specific oligonucleotide hybridization approaches to examine ras mutations without further confirmation of the positive samples by DNA sequencing. In this study, mutational hot spots in exon 1 (codons 12/13) and exon 2 (codon 61) of the H-ras, K-ras, and N-ras were polymerase chain reaction (PCR) amplified and sequenced with an automatic sequencer. ras mutations were detected in 4 of 89 (4.5%) benign and malignant thyroid tumors. Three of 8 follicular carcinomas exhibited mutations in codon 61 of H-ras, K-ras, and N-ras, respectively, and mutation at codon 61 of N-ras was found in 1 of 12 follicular adenomas. No mutations were observed in the other tumors, which included 20 nodular goiters, 5 Hürthle cell adenomas, 42 papillary carcinomas, and 2 undifferentiated carcinomas. Our results, obtained by the direct sequencing technique, indicate a lower overall prevalence of ras oncogenes in thyroid tumors than reports in earlier series. However, the frequency of ras mutations in specific histotype of thyroid tumors and their exclusive involvement of codon 61 in our series are similar to those studies utilizing DNA sequencing to detect or to confirm ras gene alterations. The selective occurrence of ras mutations in benign and malignant follicular neoplasms indicates that ras gene alterations have a specific and early role in the development of follicular type of thyroid tumors in Taiwan.

[Differentiated thyroid cancer in Arabs in northern Israel].

Prognostic factors and survival rate of 53 Arabs with differentiated carcinoma of the thyroid treated here were reviewed. Papillary carcinoma was diagnosed in 35 (66%) and follicular carcinoma in 18 (34%): the female/male ratio was 2.3/1 and the median age 32. Age, gender, tumor size, histology and tumor stage were important prognostic factors. The 20-year actuarial survival rate of the entire group was 96%. The probable reason for the high survival rate was the low median age.