No calcitonin change in a person taking dulaglutide diagnosed with pre-existing medullary thyroid cancer.

BACKGROUND: Glucagon-like peptide-1 receptor agonists, such as dulaglutide, exenatide and liraglutide, are approved to treat Type 2 diabetes mellitus. Although these drugs provide substantial glycaemic control, studies in rodents have prompted concerns about the development of medullary thyroid carcinoma. These data are reflected in the US package insert, with boxed warnings and product labelling noting the occurrence of these tumours after clinically relevant exposures in rodents, and contraindicating glucagon-like peptide-1 receptor agonist use in people with a personal or family history of medullary thyroid carcinoma, or in people with multiple endocrine neoplasia type 2. However, there are substantial differences between rodent and human responses to glucagon-like peptide-1 receptor agonists. This report presents the case of a woman with pre-existing medullary thyroid carcinoma who exhibited no significant changes in serum calcitonin levels despite treatment with dulaglutide 2.0 mg for 6 months in the Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes-5 clinical study (NCT00734474). CASE REPORT: Elevated serum calcitonin was noted in a 56-year-old woman with Type 2 diabetes mellitus at the 6-month discontinuation visit in a study of long-term dulaglutide therapy. Retroactive assessment of serum collected before study treatment yielded an elevated calcitonin level. At 3 months post-study, calcitonin level remained elevated; ultrasonography revealed multiple bilateral thyroid nodules. Eventually, medullary thyroid carcinoma was diagnosed; the woman was heterozygous positive for a germline RET proto-oncogene mutation. CONCLUSION: The tumour was not considered stimulated by dulaglutide therapy because calcitonin remained stable throughout.

Current Management of Low Risk Differentiated Thyroid Cancer and Papillary Microcarcinoma.

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.

Patients with high-risk differentiated thyroid cancer have a lower I-131 ablation success rate than low-risk ones in spite of a high ablation activity.

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.

Outcomes for patients with papillary thyroid cancer who do not undergo prophylactic central neck dissection.

BACKGROUND: The role of prophylactic central neck dissection (CND) in the management of papillary thyroid cancer (PTC) is controversial. This report describes outcomes of an observational approach in patients without clinical evidence of nodal disease in PTC. METHODS: All patients who had surgery between 1986 and 2010 without CND for PTC were identified. All patients had careful clinical assessment of the central neck during preoperative and perioperative evaluation, with any suspicious nodal tissue excised for analysis. The cohort included patients in whom lymph nodes had been removed, but no patient had undergone a formal neck dissection. Recurrence-free survival (RFS), central neck RFS and disease-specific survival (DSS) were calculated using the Kaplan-Meier method. RESULTS: Of 1798 patients, 397 (22.1 per cent) were men, 1088 (60.5 per cent) were aged 45 years or more, and 539 (30.0 per cent) had pT3 or pT4 disease. Some 742 patients (41.3 per cent) received adjuvant treatment with radioactive iodine. At a median follow-up of 46 months the 5-year DSS rate was 100 per cent. Five-year RFS and central neck RFS rates were 96.6 and 99.1 per cent respectively. CONCLUSION: Observation of the central neck is safe and should be recommended for all patients with PTC considered before and during surgery to be free of central neck metastasis.

LEADER 2: baseline calcitonin in 9340 people with type 2 diabetes enrolled in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial: preliminary observations.

AIMS: To report preliminary data on baseline serum calcitonin concentrations and associated clinical characteristics in a global population with type 2 diabetes before liraglutide or placebo randomization. METHODS: The ongoing LEADER trial has enrolled 9340 people with type 2 diabetes and at high risk of cardiovascular disease at 410 centres worldwide. People with baseline serum calcitonin ≤ 50 ng/l were randomized to liraglutide once daily or placebo and will be followed for up to 5 years. Serum calcitonin was measured at baseline and will be measured annually thereafter. An independent committee of thyroid experts will oversee calcitonin monitoring throughout the trial and will review all calcitonin concentrations ≥ 20 ng/l. RESULTS: The mean age of participants was 64.3 ± 7.2 years, 64.3% were men, and mean the body mass index was 32.5 ± 6.3 kg/m(2). The median (interquartile range) baseline serum calcitonin values were 3.9 (1.0 to >7.6) ng/l in men and 1.0 (1.0 to >1) ng/l in women. Serum calcitonin was >10 ng/l in 14.6% of men and in 0.96% of women. In sex-specific multivariable linear analysis of covariance models, a reduced glomerular filtration rate (GFR) was associated with higher serum calcitonin concentrations that were statistically significant. A 20 ml/min/1.73 m(2) decrease in estimated GFR (eGFR) was associated with a 14% increase in serum calcitonin in women and an 11% increase in men. CONCLUSIONS: In the LEADER population, the prevalence of elevated serum calcitonin concentrations at baseline was high, and there was an inverse association between eGFR and serum calcitonin concentrations.

Outcomes in patients with poorly differentiated thyroid carcinoma.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) accounts for only 1-15% of all thyroid cancers. Our objective is to report outcomes in a large series of patients with PDTC treated at a single tertiary care cancer center. METHODS: A total of 91 patients with primary PDTC were treated by initial surgery with or without adjuvant therapy at Memorial Sloan-Kettering Cancer Center from 1986 to 2009. Outcomes were calculated by the Kaplan-Meier method. Clinicopathological characteristics were compared for PDTC patients who died of disease to those who did not by the χ(2) test. Factors predictive of disease-specific survival (DSS) were calculated by univariate and multivariate analysis using the log rank and Cox proportional hazards method, respectively. RESULTS: With a median follow-up of 50 months, the 5-year overall survival and DSS were 62 and 66%, respectively. The 5-year locoregional and distant control were 81 and 59%, respectively. Of 27 disease-specific deaths, 23 (85%) were due to distant disease. Age ≥ 45 years, pathological tumor size >4 cm, extrathyroidal extension, higher pathological T stage, positive margins, and distant metastases (M1) were predictive of worse DSS on univariate analysis. Multivariate analysis showed that only pT4a stage and M1 were independent predictors of worse DSS. CONCLUSIONS: With appropriate surgery and adjuvant therapy, excellent locoregional control can be achieved in PDTC. Disease-specific deaths occurred due to distant metastases and rarely due to uncontrolled locoregional recurrence in this series.

Anaplastic thyroid carcinoma: a 25-year single-institution experience.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive solid tumors accounting for 1-5 % of primary thyroid malignancies. In this retrospective review, we aim to evaluate the prognostic factors, treatment approaches, and outcomes of patients with ATC treated at a single institution. MATERIALS AND METHODS: We retrospectively identified 95 patients with ATC from an institutional database between 1985 and 2010. A total of 83 patients with sufficient records were included in this study. Patient, tumor, and treatment characteristics were recorded. Disease-specific survival (DSS) was determined by the Kaplan-Meier method, and factors predictive of outcome were determined by univariate and multivariate analysis. RESULTS: Of the 83 patients, 41 were male and 42 were female. The median age at presentation was 60 years (range 28-89 years) with a median survival of 8 months. The 1- and 2-year DSS were 33 and 23 %, respectively. On univariate analysis, age less than 60 years, clinically N0 neck, absence of clinical extrathyroidal extension (cETE), gross total resection, and multimodality treatment were statistically significant predictors of improved survival. On multivariate analysis, absence of cETE, multimodality therapy, and gross total resection were predictors of improved outcome. CONCLUSIONS: In patients with locoregional limited disease, multimodality treatment with gross total surgical resection and postoperative radiotherapy with or without chemotherapy offers the best local control and DSS.

Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases.

BACKGROUND: Radioiodine (RAI) remains the mainstay of therapy for RAI-avid (RAIA) distant metastatic thyroid carcinoma. We previously demonstrated that RAI-refractory distant metastatic thyroid cancers commonly harbor BRAF mutations. However, the molecular profile of RAIA metastatic thyroid cancer is unknown. Here we describe the mutational profile of thyroid tumors from follicular cell-derived cancer (FCDTC) patients presenting with RAIA distant metastases. In addition, we aimed to correlate clinical outcomes of RAI therapy with clinicopathological factors and tumor mutational status. METHODS: We retrospectively identified 43 patients with FCDTC who had RAI uptake in the lungs and/or bones on their initial ¹³¹I postablation scan. Primary tumors were genotyped for known mutations in thyroid cancer genes. Structural response to RAI was assessed 6-18 months after each administered RAI activity and at the end of follow-up. RESULTS: RAS, BRAF, RET/PTC, and PIK3CA mutations were found in 42, 23, 10, and 2% of tumors, respectively, and the remaining 23% were wild type. None of these patients achieved cure after repeat RAI therapies, and most patients (54%) experienced disease progression despite repeated RAI administration. There was an increased prevalence of RAS mutations in these RAIA tumors. RAS-mutant cancers were more likely to concentrate iodine on diagnostic whole body scans. Despite this, structural response to RAI was not influenced by tumor genotype. CONCLUSIONS: RAIA metastatic FCDTC are overrepresented with RAS mutations, whereas RAI refractory metastatic thyroid cancers are enriched with BRAF mutations. Despite a seemingly preserved ability to concentrate iodine, RAI therapy is ineffective in achieving cure in most patients with RAIA metastatic FCDTC, even in RAS-mutant disease. These poor outcomes may be improved based on recent evidence that pretreatment with MAPK kinase 1/2 inhibitors enhances responses to RAI, particularly in patients with RAS-mutant tumors.

Suspicious cervical lymph nodes detected after thyroidectomy for papillary thyroid cancer usually remain stable over years in properly selected patients.

CONTEXT: The risk of loco-regional recurrence in papillary thyroid cancer (PTC) patients ranges from 15-30%. However, the clinical significance of small-volume loco-regional recurrence detected by highly sensitive ultrasonography is unclear. OBJECTIVE: Our objective was to describe the natural history of abnormal cervical lymph nodes (LN) diagnosed after initial treatment. DESIGN: We conducted a retrospective cohort study. PATIENTS: 166 PTC with patients who had at least one abnormal LN outside the thyroid be on ultrasound and selected for active surveillance were included. MAIN OUTCOME MEASURE: LN growth during a period of active surveillance was the primary outcome. RESULTS: Most patients had classical PTC (85%) and an intermediate risk of recurrence (77%). The median LN size at the start of the observation period was 1.3 cm (range, 0.5-2.7 cm) in largest diameter, with all nodes having at least one abnormal sonographic characteristic (70% of patients had LN with at least two abnormal features). In almost all patients, the LN were in the lateral neck, primarily in levels 3 (43%) and 4 (58%). After a median follow-up of 3.5 yr, only 20% (33 of 166) grew at least 3 mm, 9% (15 of 166) grew at least 5 mm, and 14% (23 of 166) resolved. None of the clinical or sonographic features were predictive of LN growth (positive predictive value range = 0.21-0.57). There were no local complications (nerve damage or local invasion) related to the abnormal nodes and no disease-related mortality. CONCLUSIONS: Suspicious cervical LN in the lateral neck usually remain stable for long periods of time in properly selected PTC patients and can be safely followed with serial ultrasounds.

Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH.

CONTEXT: Elevated levels of TSH markedly enhance the effectiveness of radioiodine (RAI) therapy in metastatic thyroid cancer. OBJECTIVE: The objective of the study was to compare short-term overall survival in thyroid cancer patients with RAI-avid distant metastases prepared for RAI therapy with either traditional thyroid hormone withdrawal (THW) or recombinant human TSH (rhTSH) stimulation. DESIGN: This was a retrospective chart review. SETTING: The study was conducted at a tertiary care comprehensive cancer center. PATIENTS: Patients included 175 patients with RAI avid metastatic disease to lung and/or bone. INTERVENTIONS: In 58 patients, all RAI treatments (remnant ablation and therapy of metastatic disease) were done with rhTSH stimulation. In 35 patients, all RAI treatments were done after THW. In 82 patients, THW was used for initial RAI treatment(s) with subsequent administered activities given after rhTSH stimulation. MAIN OUTCOME MEASURE: Overall survival was measured. RESULTS: After a median follow-up of 5.5 yr, there were no significant differences in overall survival between patients prepared for RAI therapy with rhTSH alone, THW alone, or THW followed by rhTSH (Kaplan-Meier analysis, P = 0.80). In a multivariate analysis that included clinicopathological features and method of preparation (rhTSH or TWH), only age at diagnosis was an independent predictor of overall survival. CONCLUSIONS: Preparation for RAI therapy using either THW or rhTSH stimulation was associated with similar 5-yr overall survival rates in patients with RAI avid thyroid cancer metastases to lung or bone.

Clinical presentation and clinical outcomes in Chernobyl-related paediatric thyroid cancers: what do we know now? What can we expect in the future?

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.

Contemporary post surgical management of differentiated thyroid carcinoma.

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.

Erythropoietin in thyroid cancer.

Erythropoietin (Epo) and the epo-receptor (EpoR) have been implicated in tumor growth, invasion and metastasis. We previously demonstrated Epo and EpoR expression in a small group of archived papillary thyroid cancers (PTC), but were unable to examine functional integrity using formalin-fixed tissues. In the present study, we examined the in vitro expression, induction and function of Epo and EpoR in papillary (NPA), follicular (WRO) and anaplastic (ARO-81) thyroid cancer cells. We found that all three cell lines expressed Epo and EpoR mRNA and that the hypoxia-mimetic cobalt induced Epo expression in all cell lines. None of the growth factors we examined (thyrotropin, vascular endothelial growth factor, IGF-I, or human Epo) altered Epo or EpoR gene expression. Importantly, however, administration of Epo to NPA but not WRO cells resulted in significant alterations in the expression of several mitogenic genes including cyclooxygenase-2 (COX-2), beta-casein (CSN2), wild type p53-induced gene-1 (WIG1) and cathepsin D (CTSD). Epo treated ARO-81 cells only had an increase in CSN2 expression. We conclude that Epo and EpoR are expressed by thyroid cancers and that stimulation of the Epo/EpoR signal pathway results in changes that could impact on the clinical behavior of thyroid cancers.

Serum thyrotropin (TSH) levels after recombinant human TSH injections in children and teenagers with papillary thyroid cancer.

CONTEXT: In preparation for whole body radioactive iodine scanning, recombinant human TSH (rhTSH) is usually administered as 0.9-mg i.m. injections on 2 consecutive days without regard to age, body size, or other comorbid conditions. OBJECTIVE: Our objective was to determine whether the usual adult rhTSH dosing regimen would result in excessive elevations of serum TSH in children and teenagers with thyroid cancer. DESIGN/SETTING/PATIENTS/INTERVENTIONS: A retrospective review identified 53 children and teenagers with thyroid cancer who underwent whole body radioactive iodine (RAI) scanning over a 12-yr period at two major medical centers (34 after thyroid hormone withdrawal and 19 after rhTSH treatment). MAIN OUTCOME MEASURES: The dynamic time course of changes in serum TSH after rhTSH administration and/or hypothyroid withdrawal was examined. Peak TSH levels were correlated with age, weight, and body surface area. RESULTS: The mean serum TSH at the time of RAI administration was similar in patients undergoing hypothyroid preparation (188 +/- 118 mIU/liter; range, 110-452 mIU/liter) and those treated with rhTSH (134 +/- 75 mIU/liter; range, 32-290 mIU/liter; P = 0.07). Serial determinations after rhTSH injections revealed a mean serum TSH of 268 +/- 76 mU/liter (range, 87-628) at 6 h and 130 +/- 58 mU/liter (range, 67-250) at 24 h after the initial injection, and 361 +/- 78 mU/liter (range 161-524) at 6 h and 134 +/- 44 mU/liter (range, 32-290) at 24 h after the second injection. CONCLUSIONS: The mean TSH levels achieved in children after rhTSH injections are remarkably similar to values previously reported in adults despite marked differences in clinical characteristics between children and adults. These data suggest that dose adjustments are not generally required in children and teenagers undergoing rhTSH stimulation for RAI scanning or serum-stimulated thyroglobulin determinations.

Nitrotyrosine, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) are increased in thyroid tumors from children and adolescents.

Nitric oxide (NO) is a reactive cell signal that controls vascular tone and is generated by inducible (iNOS), endothelial (eNOS) and neuronal (nNOS) NO synthase (NOS). We hypothesized that NO could be important for growth of thyroid tumors and tested this hypothesis, by staining 41 papillary thyroid carcinoma (PTC), 9 follicular thyroid carcinoma (FTC), and 15 benign thyroid lesions for iNOS, eNOS and nitrotyrosine (N-TYR). Staining intensity was determined by 2 blinded, independent examiners, and quantified from grade 1 (absent) to grade 4 (intense). Average N-TYR staining of benign adenomas (2.5+/-0.42, p=0.009), PTC (3.10+/-0.12, p=0.001), FTC (2.44+/-0.30, p=0.001), and autoimmune lesions (3.25+/-0.48, p=0.019) were greater than that of multinodular goiter (1.0 for all 3) and surrounding normal thyroid (1.1+/-0.1). Average iNOS staining of benign adenomas (2.6+/-0.37), PTC (2.7+/-0.16), FTC (2.4+/-0.26) and autoimmune lesions (3.5+/-0.29) were all greater than that of surrounding normal thyroid (1.1+/-0.1, p<0.008), but there were too few multinodular goiters to achieve a significant difference (no.=2, 3.0+/-1.0). Average eNOS staining of benign adenomas (2.9+/-0.40), multinodular goiters (3.5+/-0.5), PTC (3.24+/-0.18), FTC (3.5+/-0.50), and autoimmune lesions (2.8+/-0.6) were also greater than that of surrounding normal thyroid (mean=1.4+/-0.2, p<0.001). N-TYR staining correlated with that of vascular endothelial growth factor (VEGF, r=0.36, p=0.007) and the number of lymphocytes/high power field (r=0.39, p=0.004). Recurrent disease developed only from carcinoma with moderate-intense N-TYR staining, but there were too few recurrent tumors to achieve statistical significance (p=0.08). We conclude that NO is produced by benign adenomas, PTC and FTC suggesting that NO could be important in vascularization of thyroid tumors and autoimmune thyroid diseases.

Matrix metalloproteinase (MMP) expression by differentiated thyroid carcinoma of children and adolescents.

The factor(s) that control metastasis of thyroid carcinoma are unknown, but the matrix metalloproteinases (MMPs) are excellent candidates. MMP-1, membrane-type-1 MMP (MT1-MMP), and tissue inhibitor of MMP-1 (TIMP-1) have all been implicated, but the site of production and importance are disputed. In vitro, normal thyroid cells secrete TIMP-1, while thyroid cancer cells secrete TIMP-1 and MMP-1. However, previous pathological studies identified MMP-1 and TIMP-1 only in the stroma surrounding thyroid carcinoma. These data suggest that thyroid carcinoma or tumor-associated inflammatory cells might secrete a factor(s) which stimulates MMP-1 or TIMP-1 expression by surrounding tissues. We hypothesized that MMP-1, MT1-MMP, and TIMP-1 would be directly expressed by thyroid carcinoma and might promote invasion or metastasis. We used immunohistochemistry to determine the expression of MMP-1, MT1-MMP, and TIMP-1 in 32 papillary thyroid carcinoma (PTC), 10 follicular thyroid carcinoma (FTC) and 13 benign thyroid lesions from children and adolescents. The intensity of staining was graded from absent (grade 0) to intense (grade 3). Average MMP-1 expression (mean relative intensity units+/-SE) was significantly greater among PTC (1.97+/-0.15; p=0.004) and FTC (2.2+/-0.25; p=0.006) compared to benign lesions (1.30+/-0.15); but there was no relationship between MMP-1 expression and invasion, metastasis, or recurrence. Expression of MT1-MMP and TIMP-1 was similar for benign and malignant lesions; but recurrent PTC expressed lower levels of TIMP-1 when compared to non-recurrent PTC (p=0.049). Only the expression of TIMP-1 correlated with the presence of tumor-associated lymphocytes (r=0.35, p=0.032). We conclude that MMP-1, MT1-MMP and TIMP-1 are all expressed by thyroid carcinoma and could be important in promoting recurrence.

Thyroid carcinomas that express telomerase follow a more aggressive clinical course in children and adolescents.

With each cell division, DNA is lost from the telomeres, limiting the number of divisions, and leading to senescence. Malignant tumors maintain immortality by expressing a specific DNA repair enzyme, telomerase, that replaces this DNA. We hypothesized that tumors which express telomerase would have the highest recurrence risk and we tested this by determining telomerase expression in 27 papillary thyroid carcinomas (PTC), 5 follicular thyroid carcinomas (FTC) and 13 benign thyroid lesions from children and adolescents. Patients were 6-21 yr of age (mean+/-SE=16.6+/-4.1 yr) and followed from 0-14.1 yr (mean+/-SE=4.71+/-3.5 yr). Original tumors were sectioned, and immunostained for telomerase. Telomerase-specific staining was determined by two independent, blind examiners and graded from absent (Grade 0) to intense (Grade 3). Telomerase was detected in a similar majority of benign (11/13, 85%) and malignant tumors (24/32, 75%). However, the intensity of telomerase expression was greater among FTC (mean+/-SE=2.4+/-0.5 relative intensity) followed by PTC (mean+/-SE=1.9+/-1.0 relative intensity) and benign tumors (mean+/-SE=1.8+/-1.0 relative intensity). Autoimmune lesions had lower telomerase expression (mean+/-SE=1.25+/-0.5 relative intensity) compared to FTC (p=0.01), PTC (p=0.06) and benign lesions (p=0.15). Among PTC, 19 (70%) expressed telomerase, and 8 (30%) did not. Direct invasion (no.=4, 21%), distant metastasis (no.=2, 10%) and recurrence (no.=7, 37%) developed exclusively in PTC that expressed telomerase (p=0.02). Disease-free survival was also shorter for PTC that expressed telomerase (p=0.06). Recurrence developed in 1/2 (50%) FTC that expressed telomerase. We conclude that childhood thyroid cancers which express telomerase have an increased risk of tissue invasion, metastasis, and recurrence.