Teresa Montesano

Papillary Thyroid Cancer: Time Course of Recurrences During Postsurgery Surveillance

CONTEXT The current use of life-long follow-up in patients with papillary thyroid cancer (PTC) is based largely on the study of individuals diagnosed and treated in the latter half of the 20th century when recurrence rates were approximately 20% and relapses detected up to 20-30 years after surgery. Since then, however, diagnosis, treatment, and postoperative monitoring of PTC patients have evolved significantly. OBJECTIVES The objective of the study was to identify times to PTC recurrence and rates by which these relapses occurred in a more recent patient cohort. PATIENTS AND DESIGN We retrospectively analyzed follow-up data for 1020 PTC patients consecutively diagnosed in 1990-2008 in 8 Italian hospital centers for thyroid disease. Patients underwent thyroidectomy, with or without radioiodine ablation of residual thyroid tissue and were followed up with periodic serum thyroglobulin assays and neck sonography. RESULTS At the initial posttreatment (≤ 12 months) examination, 948 patients had no structural/functional evidence of disease. During follow-up (5.1-20.4 years; median 10.4 years), recurrence (cervical lymph nodes, thyroid bed) was diagnosed in 13 (1.4%) of these patients. All relapses occurred 8 or fewer years after treatment (10 within the first 5 years, 6 within the first 3 years). Recurrence was unrelated to the use/omission of postoperative radioiodine ablation. CONCLUSION In PTC patients whose initial treatment produces disease remission (no structural evidence of disease), recurrent disease is rare, and it usually occurs during the early postoperative period. The picture of recurrence timing during the follow-up provides a foundation for the design of more cost-effective surveillance protocols for PTC patients.

Identification and optimal postsurgical follow-up of patients with very low-risk papillary thyroid microcarcinomas

CONTEXT Most papillary thyroid microcarcinomas (PTMCs; ≤ 1 cm diameter) are indolent low-risk tumors, but some cases behave more aggressively. Controversies have thus arisen over the optimum postoperative surveillance of PTMC patients. OBJECTIVES We tested the hypothesis that clinical criteria could be used to identify PTMC patients with very low mortality/recurrence risks and attempted to define the best strategy for their management and long-term surveillance. DESIGN We retrospectively analyzed data from 312 consecutively diagnosed PTMC patients with T1N0M0 stage disease, no family history of thyroid cancer, no history of head-neck irradiation, unifocal PTMC, no extracapsular involvement, and classic papillary histotypes. Additional inclusion criteria were complete follow-up data from surgery to at least 5 yr after diagnosis. All 312 had undergone (near) total thyroidectomy [with radioactive iodine (RAI) remnant ablation in 137 (44%) - RAI group] and were followed up yearly with cervical ultrasonography and serum thyroglobulin, TSH, and thyroglobulin antibody assays. RESULTS During follow-up (5-23 yr, median 6.7 yr), there were no deaths due to thyroid cancer or reoperations. The first (6-12 months after surgery) and last postoperative cervical sonograms were negative in all cases. Final serum thyroglobulin levels were undetectable (<1 ng/ml) in all RAI patients and almost all (93%) of non-RAI patients. CONCLUSION Accurate risk stratification can allow safe follow-up of most PTMC patients with a less intensive, more cost-effective protocol. Cervical ultrasonography is the mainstay of this protocol, and negative findings at the first postoperative examination are highly predictive of positive outcomes.

Clinical aggressiveness and long-term outcome in patients with papillary thyroid cancer and circulating anti-thyroglobulin autoantibodies.

OBJECTIVE The association between papillary thyroid cancer (PTC) and Hashimotos thyroiditis is widely recognized, but less is known about the possible link between circulating anti-thyroglobulin antibody (TgAb) titers and PTC aggressiveness. To shed light on this issue, we retrospectively examined a large series of PTC patients with and without positive TgAb. METHODS Data on 220 TgAb-positive PTC patients (study cohort) were retrospectively collected in 10 hospital-based referral centers. All the patients had undergone near-total thyroidectomy with or without radioiodine remnant ablation. Tumor characteristics and long-term outcomes (follow-up range: 2.5-24.8 years) were compared with those recently reported in 1020 TgAb-negative PTC patients with similar demographic characteristics. We also assessed the impact on clinical outcome of early titer disappearance in the TgAb-positive group. RESULTS At baseline, the study cohort (mean age 45.9 years, range 12.5-84.1 years; 85% female) had a significantly higher prevalence of high-risk patients (6.9% vs. 3.2%, p<0.05) and extrathyroidal tumor extension (28.2% vs. 24%; p<0.0001) than TgAb-negative controls. Study cohort patients were also more likely than controls to have persistent disease at the 1-year visit (13.6% vs. 7.0%, p=0.001) or recurrence during subsequent follow-up (5.8% vs. 1.4%, p=0.0001). At the final follow-up visit, the percentage of patients with either persistent or recurrent disease in the two cohorts was significantly different (6.4% of TgAb-positive patients vs. 1.7% in the TgAb-negative group, p<0.0001). At the 1-year visit, titer normalization was observed in 85 of the 220 TgAb-positive individuals. These patients had a significantly lower rate of persistent disease than those who were still TgAb positive (8.2% vs. 17.3%. p=0.05), and no relapses were observed among patients with no evidence of disease during subsequent follow-up. CONCLUSIONS PTC patients with positive serum TgAb titer during the first year after primary treatment were more likely to have persistent/recurrent disease than those who were consistently TgAb-negative. Negative titers at 1 year may be associated with more favorable outcomes.

Identification of viable myocardium in patients with chronic coronary artery disease and left ventricular dysfunction: role of magnetic resonance imaging.

Nineteen patients (16 men and 3 women, mean age 51 years) with previous anterior myocardial infarction and severe stenosis (> or = 90%) of the left anterior descending coronary artery were studied by magnetic resonance imaging (MRI) without and with contrast media to verify the capability of MRI in identifying viable myocardium in areas of severe systolic dysfunction. In corresponding left ventricular segments, a comparison was made between regional signal intensities (SI) determined on MRI images before and 4, 8, 12, and 30 minutes after administration of paramagnetic contrast media (gadolinium diethylenetriaminepentaacetic acid, 0.4 mmol/kg intravenously) and metabolic parameters determined by iodine 123 phenylpentadecanoic acid (IPPA) scintigraphy. The SI and the time of maximum postcontrast enhancement were analyzed by dividing the left ventricle into 11 segments. Each segment was classified as normal (group 1, n = 116), hibernating (group 2, n = 50), or necrotic (group 3, n = 43) on the basis of the IPPA washout rate (> 30%, 10% to 30%, and < 10%, respectively). Regional SI demonstrated significant differences in absolute values at 12 minutes (group 3: 1.62 +/- 0.58 vs group 1: 1.32 +/- 0.52, p < 0.01, and vs group 2: 1.34 +/- 0.48, p < 0.05) and at 30 minutes (group 3: 1.71 +/- 0.47 vs group 1: 1.21 +/- 0.55, p < 0.01, and vs group 2: 1.49 +/- 0.57, p < 0.05) and in temporal distribution. These results suggest that MRI has a potential role in differentiating viable from necrotic myocardium in patients with chronic severe systolic dysfunction.

Death from differentiated thyroid carcinoma: Retrospective study of a 40-year investigation

Differentiated thyroid carcinoma (DTC) usually has a good prognosis, but sometimes the course of the disease results in death. The aim of the present study was to assess the effect of some variables in time to death on fatal cases in our series. A total of 83 patients with DTC who died between 1958 and 1998 from differentiated thyroid cancer were retrospectively analyzed with respect to gender, age at diagnosis, histology, percentage of (131)I uptake by postoperative thyroid remnant, site of tumor growth, and its (131)I uptake, metastases and time to death. Univariate analysis revealed a significantly shorter time to death in local recurrence when comparing local lymph node metastases and distant metastases even if neither show (131)I uptake. Multivariate analysis revealed that age at diagnosis was the most important factor in conditioning the time to death. In conclusion, in those patients who died from DTC an older age at diagnosis and presence of local recurrence influenced the time to death independently of (131)I uptake.

Lack of association between obesity and aggressiveness of differentiated thyroid cancer

PurposeAim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort.MethodsPatients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score.ResultsThe cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman’s ρ − 0.02; p = 0.71) and ATA Initial Risk Stratification System score (ρ 0.03; p = 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate–high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06).ConclusionsObesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.

8th edition of the AJCC/TNM staging system of thyroid cancer: what to expect (ITCO#2)

Differentiated thyroid cancer (DTC) has become one of the most frequently diagnosed malignancies, especially among women and young adults (Davies & Welch 2014). The outcomes are generally very good: disease recurrence rates are low (Durante et al. 2013), and survival rates are excellent (Tuttle et al. 2017a). Evidence-based management is crucial to avoid overtreatment of these low-risk tumors, which can reduce quality of life and yet identify accurately those requiring more aggressive therapy. Several staging systems have been generated to inform DTC management. One of the most widely used is the tumor-node-metastasis (TNM) classification elaborated by the American Joint Committee on Cancer (AJCC), which allows to predict the risk of cancer-related death. The 8th edition of the AJCC staging system for thyroid cancer (AJCC-8) was recently published (Tuttle et al. 2017b) and is scheduled to be implemented on 1 January 2018. Revision of the system was undertaken to address several specific limitations identified in the 7th edition (AJCC-7), which has been in use since 2009 (Tuttle et al. 2017a,b). The main changes (described in detail below and summarized in Table 1) are as follows: (1) an increase in the age threshold for defining high risk of thyroid cancer-related death and (2) a decrease in the unfavorable prognostic significance attributed to certain findings (i.e., cervical lymph node metastases and microscopic extrathyroidal extension (ETE), which has been re-defined to include only invasion of the perithyroidal muscle). To assess the impact of transitioning to the new AJCC-8 in terms of stage distribution and prevalence of each stage class, we analyzed data extracted from the web-based database of the Italian Thyroid Cancer Observatory (ITCO) (www.itcofoundation.org), a network of thyroid cancer centers (including primary and tertiary centers) located throughout Italy. The database includes prospectively updated, observational data provided by ITCO member centers on patients consecutively diagnosed with thyroid cancer since 2013 (Lamartina et al. 2017). Cases included in our study met all the following criteria: (1) histological diagnosis of thyroid cancer of follicular origin; (2) date of diagnosis between 1 January 2013 and 1 March 2017; (3) complete data on primary tumor pathology, including minimal ETE, and initial treatment. The selected cohort analyzed included 1765 patients, 76% of whom were females. The median age at diagnosis was 48 years (range: 10–87). Total thyroidectomy (or lobectomy + completion thyroidectomy) was performed in 1727 (98%) cases and followed by radioiodine remnant ablation in 954 (55%). Neck dissection was performed in 711 (40%) of the 1765 patients. Most of the tumors (n = 1657, 94%) were papillary thyroid cancers; the remaining 108 (6%) were follicular or Hürthle cell carcinomas. Estimated risks of recurrence calculated according to the criteria recommended in 2015 by the American Thyroid Association were low in 1046 (59%), intermediate in 612 (35%) and high in 107 (6%) of the cases. Microscopic ETE was found in 410 (23%), but only 40 (2%) of these patients had gross invasion of the strap muscles (sternohyoid, sternothyroid, thyroidhyoid and/or omohyoid muscles). Lymph node status for the 711 patients who underwent lymph node dissection was as follows: pN0 (no metastasis) in 338 (19%); pN1a (central compartment metastases) in 221 (12%) and pN1b (lateral compartment metastases) 152 (9%). Distant metastases were found in 32 (1.8%) patients. As noted above, in the AJCC-8, the age threshold for high risk of disease-specific mortality was raised from 45 years – the median age at diagnosis in several published series – to 55 years (Nixon et al. 2016). This change increases the proportion of relatively young patients whose mortality risk can be defined solely on the basis of the absence or presence of distant metastases (stages I and II, respectively) (Table 1). As shown in Fig. 1A, the percentage of patients classified as ‘younger’ in our 3 25

Are Evidence-Based Guidelines Reflected in Clinical Practice? An Analysis of Prospectively Collected Data of the Italian Thyroid Cancer Observatory

OBJECTIVES The goal of evidence-based practice guidelines is to optimize the management of emerging diseases, such as differentiated thyroid cancer (DTC). The aim of this study was to assess therapeutic approaches for DTC in Italy and to see how closely these practices conformed to those recommended in the 2009 American Thyroid Association (ATA) guidelines. METHODS The Italian Thyroid Cancer Observatory was established to collect data prospectively on thyroid cancers consecutively diagnosed in participating centers (uniformly distributed across the nation). Data on the initial treatment of all pathologically confirmed DTC cases present in the database from January 1, 2013 (database creation) to January 31, 2016, were analyzed. RESULTS A total of 1748 patients (77.2% females; median age 48.1 years [range 10-85 years]) were enrolled in the study. Most (n = 1640; 93.8%) were papillary carcinomas (including 84 poorly differentiated/aggressive variants); 6.2% (n = 108) were follicular and Hürthle cell carcinomas. The median tumor diameter was 11 mm (range 1-93 mm). Tumors were multifocal in 613 (35%) and presented extrathyroidal extension in 492 (28%) cases. Initial treatments included total thyroidectomy (involving one or two procedures; n = 726; 98.8%) and lobectomy (n = 22; 1.2%). A quarter of the patients who underwent total thyroidectomy had unifocal, intrathyroidal tumors ≤1 cm (n = 408; 23.6%). Neck dissection was performed in 40.4% of the patients (29.5% had central compartment dissection). Radioiodine remnant ablation (RRA) was performed in 1057 (61.2%) of the 1726 patients who underwent total thyroidectomy: 460 (41.2%) of the 983 classified by 2009 ATA guideline criteria as low-risk, 570 (87.1%) of the 655 as intermediate-risk, and 82 (93.1%) of the 88 as high-risk patients (p < 0.001). RRA was performed in 44% of the cases involving multifocal DTCs measuring ≤1 cm. CONCLUSIONS The treatment approaches for DTCs used in Italy display areas of inconsistency with those recommended by the 2009 ATA guidelines. Italian practices were characterized by underuse of thyroid lobectomy in intrathyroidal, unifocal DTCs ≤1 cm. The use of RRA was generally consistent with risk-stratified recommendations. However, its frequent use in small DTCs (≤1 cm) that are multifocal persists, despite the lack of evidence of benefit. These data provide a baseline for future assessments of the impact of international guidelines on DTC management in Italy. These findings also illustrate that the dissemination and implementation of guideline recommendations, and the change in practice patterns, require ongoing education and time.

Phalangeal quantitative ultrasound and bone mineral density in evaluating cortical bone loss: a study in postmenopausal women with primary hyperparathyroidism and subclinical iatrogenic hyperthyroidism.

Twenty-five postmenopausal women with primary hyperparathyroidism (PHPT) and 30 age-matched women with subclinical hyperthyroidism (sHTH) were studied to assess cortical bone loss. One hundred two healthy women were also recruited. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry at lumbar spine (LS), femoral neck (FN) and femoral total (FT), and at one-third of the radius (R). Amplitude-dependent speed of sound (ADSoS) and Ultrasound Bone Profile Index (UBPI) were also evaluated using phalangeal quantitative ultrasound (QUS). A significant correlation was found between QUS and BMD at LS (ADSoS, p < 0.05) and R (ADSoS and UBPI, p < 0.001) in controls. QUS significantly correlated with BMD at LS, FN (p < 0.01), and FT (p < 0.001) in sHTH. No correlations were found in the PHPT group. Mean T-score values of all parameters were significantly lower in patients compared with controls (p < 0.001); however, they did not differ between PHPT and sHTH patients. T-score of R, ADSoS, and UBPI was reduced compared with other sites (p < 0.001) in both diseases. In postmenopausal women with PHPT and sHTH, bone loss is mainly detectable at cortical level. However, qualitative and/or structural changes of bone could account for the lack of correlations between these 2 techniques at cortical sites.

Sonographic Presentation of Metastases to the Thyroid Gland: A Case Series

Abstract Incidental sonographic discovery of thyroid nodules is an increasingly common event. The vast majority is benign, and those that are malignant, are generally associated with an indolent course and low mortality. Sonographic scoring systems have been developed to help clinicians identify nodules that warrant prompt fine-needle aspiration cytology (FNAC), but they are based largely on experience with papillary thyroid cancers. We analyzed the performance of four scoring systems widely used for this purpose (American Thyroid Association Guidelines, American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi Guidelines, European Thyroid Imaging Reporting and Data System, and Korean Thyroid Imaging Reporting and Data System) in patients whose nodules proved to be metastases from other solid cancers. Such nodules reportedly account for 0.2% to 3% of all thyroid malignancies. Each scoring system was used to assess retrospectively the malignancy risk and indications for FNAC of five patients’ thyroid nodules that were ultimately diagnosed as metastases (from renal cell carcinoma, breast cancer, and lung cancer in two cases and esophageal cancer). The primaries identified in these cases are those most commonly reported to metastasize to the thyroid. In two cases, the thyroid metastases were the first sign of undetected neoplastic disease. Although sonography alone cannot distinguish thyroid metastases from primary thyroid malignancies, all four scoring systems classified the metastatic nodules as suspicious enough to require FNAC. The five cases accounted for 0.2% of those cytologically examined in our center. In most cases, cytology provided useful guidance for the subsequent management of these lesions, which differs from that of primary thyroid cancers and requires multidisciplinary input.