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Each year, the proportion of thyroid cancer patients presenting with low risk disease is increasing. Moreover, the definition of low risk thyroid cancer is expanding and several histological subtypes beyond papillary microcarcinomas are now classified as low risk disease. This shift in the landscape of thyroid cancer presentation is forcing clinicians to critically re-evaluate whether or not traditional management paradigms that were effective in treating intermediate and high risk disease are applicable to these low risk patients. Here we review the definition of low risk disease, examine the various histological subtypes that are considered low risk in the 2015 American Thyroid Association guidelines for the management of thyroid nodules and thyroid cancer, and review our current approach to the management of these low risk tumours., (Copyright © 2016. Published by Elsevier Ltd.)

Objective: To examine success rates in strictly defined high-risk differentiated thyroid cancer (DTC) patients who received a high-activity (≥5550 MBq) adjuvant postoperative I-131 therapy and compare these to the rates found in highest risk and low-risk patients., Design: Retrospective database study., Patients: We examined 377 patients with DTC who received I-131 ablation. Patients with distant metastases were classified as very high risk. Patients with primary tumours >4 cm, extensive extrathyroidal invasion (pT4a or pT4b in accordance with the 7th edition of the TNM system), and patients with ≥5 lymph node metastases or any lateral compartment lymph node metastases were considered high risk. All other patients were considered low risk., Measurements: Ablation success rate at first TSH-stimulated follow-up., Results: The ablation success rate was 72·6% in low-risk patients, 51·7% in high-risk patients and 13·8% in highest risk patients (all differences P < 0·001). In none of the groups, a significant difference in the initial I-131 activity was found between patients with successful and unsuccessful ablation (low risk: P = 0·16, high risk: P = 0·91 and highest risk: P = 0·48). Furthermore, there was no difference in ablation success between patients who received <5550 MBq and those who received ≥5550 Mbq (low risk: P = 0·31, high risk: P = 0·69 and highest risk: P = 0·22)., Conclusions: Patients with high-risk DTC have a significantly reduced I-131 ablation success rate compared to low-risk ones in spite of high initial I-131 activities. As successful ablation is prognostically important, efforts should be made to improve outcome in these patients., (© 2016 John Wiley & Sons Ltd.)

Over the last 20 years, nearly 5000 cases of differentiated thyroid cancer have been diagnosed and treated in the regions of Russia, Ukraine and Belarus in young people previously exposed to the Chernobyl radioactive fallout during childhood. At diagnosis, 60-70% of the Chernobyl-related paediatric thyroid cancers had clinically evident cervical lymph node metastases (N1) and 10-15% had distant metastases (M1). Despite early reports suggesting that the paediatric thyroid cancer cases that developed after exposure to Chernobyl fallout were particularly aggressive, it now seems that the initial presentation and early clinical course of most of these cases are very similar to both non-radiation-associated paediatric thyroid cancers and thyroid cancers that arise after exposure to external beam irradiation. Over an average clinical follow-up period of about 10 years, the disease-specific mortality rate in these paediatric thyroid cancer cases that developed after the Chernobyl accident is quite low (1% or less). As would be expected in paediatric thyroid cancer, short-term recurrence rates range from 7 to 28% in published reports (mean 17%). However, long-term studies of paediatric thyroid cancer suggest that although the 30 year disease-specific mortality rate should be about 1%, the risk of developing structural disease recurrence is nearly 30% (of which 80% are expected to be locoregional recurrences and 20% are probably new distant metastases). Projected over 30 years of follow-up, a 1% disease-specific mortality in this cohort of 5000 patients would equate to about 50 deaths directly attributable to thyroid cancer. However, a 30% recurrence rate would also mean that about 1500 patients may develop a clinically meaningful recurrence that would need to be diagnosed and treated. It is imperative that we continue to work with our colleagues in Belarus, Ukraine and Russia to ensure that this large volume of patients destined to develop clinically significant recurrences are diagnosed and treated in a timely manner. Ready access to modern disease detection tools (serum thyroglobulin, postoperative neck ultrasonography, cytology/pathology support, and radioactive iodine scanning) and treatments (surgery for recurrent disease, radioactive iodine therapy) in their major academic centres are mandatory if we expect to achieve the excellent clinical outcomes that should be seen when paediatric thyroid cancer recurrence is diagnosed early and treated appropriately., (Copyright © 2011 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Risk assessment is the cornerstone of contemporary management of thyroid cancer. Following thyroid surgery, an initial risk assessment of recurrence and disease-specific mortality is made using important intra-operative findings, histologic characteristics of the tumor, molecular profile of the tumor, post-operative serum thyroglobulin and any available cross-sectional imaging studies. This initial risk assessment is used to guide recommendations regarding the need for remnant ablation, external beam irradiation, systemic therapy, degree of TSH suppression, and follow-up disease detection strategy over the first 2 years after initial therapy. While this initial risk stratification provides valuable information, it is a static representation of the patient in the first few weeks post-operatively that does not change over time. Depending on how the patient responds to our initial therapies, the risk of recurrence and death may change significantly during follow-up. In order to account for differences in response to therapy in individual patients and to incorporate the impact of treatment on our initial risk estimates, we recommend a re-stratification of risk at the 2-year point of follow-up. This re-stratification provides an updated risk estimate that can be used to guide ongoing management recommendations including the frequency and intensity of follow-up, degree of ongoing TSH suppression, and need for additional therapies. Ongoing management recommendations must be tailored to realistic, evolving risk estimates that are actively updated during follow-up. By individualizing therapy on the basis of initial and ongoing risk assessments, we can maximize the beneficial effects of aggressive therapy in patients with thyroid cancer who are likely to benefit from it, while minimizing potential complications and side effects in low-risk patients destined to have a full healthy and productive life after minimal therapeutic intervention., (Copyright (c) 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Radioactive iodine (131I) is an important therapeutic option for the treatment of metastatic thyroid carcinoma. Survival in patients with metastases that concentrate radioiodine is better than those whose metastatic lesions do not take up radioiodine. Survival is markedly reduced in patients who have metastatic lesions that concentrate 18F-fluorodeoxyglucose (FDG) on positron emission tomography (PET). In this retrospective study, we evaluated the ability of 131I to destroy FDG-avid metastatic lesions in thyroid cancer patients. Twenty-five patients with positive FDG-PET scans received at least one dose of 131I treatment before a second FDG-PET was performed. The average interval between the two PET scans was 12.9 months. The average interval between the 131I treatment and the follow-up FDG-PET was 10.1 months. We measured posttherapy changes in lesional volume, in standard uptake values (SUV) of FDG, and in serum thyroglobulin (Tg) levels. The total volume of FDG-avid metastases rose significantly (p = 0.036) from a mean of 159 mL to 235 mL after 131I therapy, the maximum SUV rose from 9.3 to 11.9, the median Tg at the time of the second PET scan was 132% of that at baseline. Statistical analyses demonstrated no significant changes in maximum SUV, or serum Tg levels after 131I in the FDG-PET-positive group. In a control group of FDG-PET-negative patients, the serum Tg decreased to 38% of baseline after 131I therapy (p < 0.001). We conclude that high-dose 131I therapy appears to have little or no effect on the viability of metastatic FDG-avid thyroid cancer lesions.

Radioiodine ablation (RA) of normal thyroid remnants after thyroidectomy for differentiated thyroid carcinoma improves the sensitivity of subsequent radioiodine scans and serum thyroglobulin measurements for detection of residual thyroid carcinoma. Local cancer recurrences are also lower after RA. One standard preparation for RA involves rendering the patient hypothyroid in order to stimulate endogenous thyrotropin (TSH) secretion and sodium iodide symporter (NIS) activity. An alternative approach is to prescribe thyroxine after thyroidectomy and to stimulate NIS with exogenous recombinant human thyrotropin (rhTSH). This latter approach was used in 10 patients at our medical center. Complete resolution of all visible 131I thyroid bed uptake was achieved in all when follow-up scans were performed 5 to 13 months later. This approach has the potential to successfully ablate thyroid remnants without the need to induce hypothyroidism.

Thyroid transcription factor 1 (TTF-1) is essential for thyroid differentiation and regulates expression of thyroglobulin, thyroid peroxidase, sodium/iodide symporter, and thyrotropin receptor (TSH-R) genes. Because thyrotropin (TSH) upregulates these same genes, we hypothesized TSH-R activation might increase TTF-1 and that TTF-1 might be differentially expressed in benign and malignant thyroid disease. TTF-1 expression and sub-cellular localization were determined by immunohistochemistry in 62 thyroid carcinomas, 15 benign lesions, and 2 normal thyroids. Nuclear TTF-1 was detected in benign (77%) and malignant lesions (69%), with similar intensity in both (1.1+/-0.19 versus 1.0+/-0.10). Nuclear TTF-1 staining correlated with the effective serum TSH level (p = 0.02) and patient age (p < 0.05). Nuclear TTF-1 was detected in 35 papillary thyroid carcinomas (PTC), of which 23% developed recurrent or persistent disease, and was absent from 18 PTC, of which only 6% recurred (p = 0.06). We conclude that nuclear TTF-1 correlates with serum TSH activity, increases with age, and may be increased in persistent or recurrent PTC.

Background: Vascular endothelial growth factor (VEGF) induces proliferation of endothelial cells, stimulates angiogenesis, and increases vascular permeability. Increased VEGF expression has been associated with poor clinical outcomes in many malignancies. Several recent reports have documented over expression of VEGF in papillary thyroid cancer. We hypothesized that increased expression of VEGF would be associated with either an increased risk of recurrence or a decreased recurrence-free survival in papillary thyroid cancer., Methods: Immunohistochemistry was used to detect VEGF expression in archival paraffin-embedded surgical thyroid specimens from 96 subjects with papillary thyroid cancer., Results: VEGF expression was detected in 98% (94/96) of the samples, predominantly of slight-to-moderate intensity in the majority of malignant cells. However, the specific finding of a diffuse pattern of intense immunostaining for VEGF was detected significantly more often than less intense, patchy immunostaining patterns in subjects with distant metastasis at diagnosis (63% versus 15%, P =.005), local recurrence (58% versus 13%, P =.001), and distant recurrence (83% versus 14%, P =.001). Furthermore, this specific pattern of diffuse, intense VEGF expression was associated with a significantly shorter recurrence-free survival than other staining patterns (P =.007)., Conclusions: These data demonstrate that the immunohistochemical pattern of VEGF staining in the initial surgical specimen is strongly associated with the incidence of local and distant metastasis in papillary thyroid cancer.

Altered expression of the gene encoding the sodium iodine symporter (NIS) may be an important factor that leads to the reduced iodine accumulation characteristic of most benign and malignant thyroid nodules. Both up- and down-regulation of NIS gene expression have been reported in thyroid cancer using several different methods. The goal of the present study was to accurately identify alterations in NIS gene expression in benign and malignant thyroid nodules using an accurate real-time quantitative RT-PCR assay system. Total RNA was prepared from 18 benign thyroid nodules, 20 papillary thyroid cancers, and 23 normal thyroid samples from 38 subjects. Quantitative RT-PCR was used to measure NIS and thyroglobulin (TG) mRNA expression in normal thyroid tissue and in each nodular tissue sample. Papillary thyroid cancer samples had significantly lower NIS mRNA expression (72 +/- 41 picogram equivalents [pg Eq]), than did benign nodules (829 +/- 385 pg Eq), or normal tissues (1907 +/- 868 pg Eq, P = 0.04). Most important, in the paired samples, NIS gene expression was decreased in each papillary thyroid cancer compared with normal tissue (69% median decrease; range, 40-96%; P = .013). Eleven of the 12 benign nodules also demonstrated lower NIS gene expression than the normal tissue (49% decrease; range, 2-96%; P = .04). Analysis of the paired samples demonstrated that Tg mRNA expression was significantly lower in each of the thyroid cancer samples than in corresponding normal tissue (759 +/- 245 pg Eq vs. 1854 +/- 542 pg Eq, P = .03). We have demonstrated a significant decrement in NIS gene expression in all papillary thyroid cancers and in over 90% of benign nodules examined compared with adjacent normal thyroid tissue, using a highly accurate quantitative RT-PCR technique. Similarly, thyroid cancers demonstrated significantly lower TG mRNA expression than corresponding normal thyroid. Reduced NIS expression may be an important factor in the impairment of iodine-concentrating ability of neoplastic thyroid tissues.

Reverse transcriptase-PCR has identified thyroglobulin mRNA (Tg mRNA) in peripheral blood of normal adults and adults with thyroid cancer. However, no children were studied. The primary objective of this study was to determine whether whole blood Tg mRNA levels differ between benign and malignant thyroid disease in children. The secondary goals were to determine whether whole blood Tg mRNA levels vary with age or pubertal development among children with thyroid disease. Whole blood Tg mRNA levels were determined in 38 children (29 girls, nine boys; median age, 14.5 y; range, 4.8-20.4 y) with benign and malignant thyroid disease and correlated with diagnosis, age, pubertal status, thyroid size, and serum levels of free thyroxine, TSH, and Tg protein. Tg mRNA levels ranged from 3.3 to 104 pg Eq/microg total thyroid RNA (mean, 28 +/- 20.2 pg Eq/microg total thyroid RNA) and were similar in benign and malignant disorders (p = 0.67). However, in children with previously treated papillary thyroid cancer, Tg mRNA levels directly correlated with total body (131)I uptake (p = 0.026) and serum Tg protein (p = 0.037). There was no difference between boys and girls, and no change with pubertal maturation. In children with benign thyroid disease, Tg mRNA levels correlated with serum TSH (p = 0.031), but not with diagnosis, age, Tanner stage, or thyroid size. We conclude that Tg mRNA levels are similar in children with benign and malignant thyroid disease and unchanged by age or pubertal status, but correlated with tumor burden in previously treated papillary thyroid cancer.