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ContextFor the correct clinical application of the sonographic risk-stratification systems, the definition of independent risk features that are foundational to each system is crucial.ObjectiveThe aim of this study was to identify the gray-scale sonographic features independently associated with malignancy, and to compare different definitions.MethodsThis prospective, diagnostic accuracy study took place in a single thyroid nodule referral center. All patients consecutively referred to our center for fine-needle aspiration cytology of a thyroid nodule between November 1, 2015 and March 30, 2020, were enrolled before cytology. Each nodule was examined by 2 experienced clinicians to record the sonographic features on a rating form. Histologic (when available) or cytologic diagnosis was used as the reference standard. For each single sonographic feature and definition, the sensitivity, specificity, positive and negative predictive values, and diagnostic odds ratios (DOR) were calculated. The significant predictors were then included in a multivariable regression model.ResultsThe final study cohort consisted of 903 nodules in 852 patients. A total of 76 nodules (8.4%) were malignant. Six features were independent predictors of malignancy: suspicious lymph node (DOR 16.23), extrathyroidal extension (DOR 6.60), irregular or infiltrative margins (DOR 7.13), marked hypoechogenicity (DOR 3.16), solid composition (DOR 3.61), and punctate hyperechoic foci (including microcalcifications and indeterminate foci; DOI 2.69). Taller-than-wide shape was not confirmed as an independent predictor.ConclusionWe identified the key suspicious features of thyroid nodules and provided a simplified definition of some debated ones. Malignancy rate increases with number of features.

ContextThe risk stratification of patients with differentiated thyroid cancer (DTC) is crucial in clinical decision making. The most widely accepted method to assess risk of recurrent/persistent disease is described in the 2015 American Thyroid Association (ATA) guidelines. However, recent research has focused on the inclusion of novel features or questioned the relevance of currently included features.ObjectiveTo develop a comprehensive data-driven model to predict persistent/recurrent disease that can capture all available features and determine the weight of predictors.MethodsIn a prospective cohort study, using the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339), we selected consecutive cases with DTC and at least early follow-up data (n = 4773; median follow-up 26 months; interquartile range, 12-46 months) at 40 Italian clinical centers. A decision tree was built to assign a risk index to each patient. The model allowed us to investigate the impact of different variables in risk prediction.ResultsBy ATA risk estimation, 2492 patients (52.2%) were classified as low, 1873 (39.2%) as intermediate, and 408 as high risk. The decision tree model outperformed the ATA risk stratification system: the sensitivity of high-risk classification for structural disease increased from 37% to 49%, and the negative predictive value for low-risk patients increased by 3%. Feature importance was estimated. Several variables not included in the ATA system significantly impacted the prediction of disease persistence/recurrence: age, body mass index, tumor size, sex, family history of thyroid cancer, surgical approach, presurgical cytology, and circumstances of the diagnosis.ConclusionCurrent risk stratification systems may be complemented by the inclusion of other variables in order to improve the prediction of treatment response. A complete dataset allows for more precise patient clustering.

Context Approximately 60% of adults harbor 1 or more thyroid nodules. The possibility of cancer is the overriding concern, but only about 5% prove to be malignant. The widespread use of diagnostic imaging and improved access to health care favor the discovery of small, subclinical nodules and small papillary cancers. Overdiagnosis and overtreatment is associated with potentially excessive costs and nonnegligible morbidity for patients. Evidence Acquisition We conducted a PubMed search for the recent English-language articles dealing with thyroid nodule management. Evidence Synthesis The initial assessment includes an evaluation of clinical risk factors and sonographic examination of the neck. Sonographic risk-stratification systems (e.g., Thyroid Imaging Reporting and Data Systems) can be used to estimate the risk of malignancy and the need for biopsy based on nodule features and size. When cytology findings are indeterminate, molecular analysis of the aspirate may obviate the need for diagnostic surgery. Many nodules will not require biopsy. These nodules and those that are cytologically benign can be managed with long-term follow-up alone. If malignancy is suspected, options include surgery (increasingly less extensive), active surveillance or, in selected cases, minimally invasive techniques. Conclusion Thyroid nodule evaluation is no longer a 1-size-fits-all proposition. For most nodules, the likelihood of malignancy can be confidently estimated without resorting to cytology or molecular testing, and low-frequency surveillance is sufficient for most patients. When there are multiple options for diagnosis and/or treatment, they should be discussed with patients as frankly as possible to identify an approach that best meets their needs.

Context Ultrasonography (US) is considered the most sensitive tool for imaging persistent or recurrent papillary thyroid cancer (PTC) in the neck. Objective To clarify the usefulness of routine neck US in low- and intermediate-risk patients with PTC with no evidence of disease 1 year after thyroidectomy. Design Retrospective analysis of prospectively recorded data. Setting Academic center. Patients Two hundred twenty-six patients with PTC with sonographically normal neck lymph nodes and unstimulated serum thyroglobulin (Tg) levels that were either undetectable ( Interventions Yearly assessment: unstimulated serum Tg level, anti-Tg-antibody (TgAb) titer, TSH levels, and ultrasound examination of neck lymph nodes. Main Outcome Measures Rates of ultrasonographic lymph node abnormalities at the 3-year and last follow-up visits. Results In patients with an undetectable Tg level at the 1-year evaluation, sonographically suspicious neck lymph nodes were found in 1.2% of patients at 3 years and in 1.8% at the last visit [negative predictive values (NPVs) of 1-year Tg < 0.2 ng/mL: 98.8% (95% CI 95.8% to 99.9%) and 98.2% (95% to 99.6%), respectively]. Similar NPVs emerged for low detectable 1-year Tg levels [98.2% (90.3% to 99.9%) and 94.5% (84.9% to 98.9%) at the 3-year and last visits, respectively]. Seventy-five percent of the nodal lesions were likely false positive; none required treatment. Conclusions Low- and intermediate-risk patients with PTC with negative ultrasound findings and unstimulated Tg levels

Context:The European Thyroid Association (ETA) has classified posttreatment cervical ultrasound findings in thyroid cancer patients based on their association with disease persistence/recurrence.Objective:The objective of the study was to assess this classification's ability to predict the growth and persistence of such lesions during active posttreatment surveillance of patients with differentiated thyroid cancer (DTC).Design:This was a retrospective, observational study.Setting:The study was conducted at a thyroid cancer center in a large Italian teaching hospital.Patients:Center referrals (2005–2014) were reviewed and patients selected with pathologically-confirmed DTC; total thyroidectomy, with or without neck dissection and/or radioiodine remnant ablation; abnormal findings on two or more consecutive posttreatment neck sonograms; and subsequent follow-up consisting of active surveillance. Baseline ultrasound abnormalities (thyroid bed masses, lymph nodes) were classified according to the ETA system. Patients were divided into group S (those with one or more lesions classified as suspicious) and group I (indeterminate lesions only). We recorded baseline and follow-up clinical data through June 30, 2015.Main Outcomes:The main outcomes were patients with growth (>3 mm, largest diameter) of one or more lesions during follow-up and patients with one or more persistent lesions at the final visit.Results:The cohort included 58 of the 637 DTC cases screened (9%). A total of 113 lesions were followed up (18 thyroid bed masses, 95 lymph nodes). During surveillance (median 3.7 y), group I had significantly lower rates than group S of lesion growth (8% vs 36%, P = .01) and persistence (64% vs 97%, P = .014). The median time to scan normalization was 2.9 years.Conclusions:The ETA's evidence-based classification of sonographically detected neck abnormalities can help identify papillary thyroid cancer patients eligible for more relaxed follow-up.

Radioiodine remnant ablation (RRA) has traditionally been one of the cornerstones of differentiated thyroid cancer (DTC) treatment. The decision to use RRA in low-risk (LR) and intermediate-risk (IR) patients is controversial. The aim of this review is to examine the evidence of RRA benefit in the staging, follow-up, and recurrence prevention in LR and IR DTC patients.From a PubMed search, we selected original papers (OPs) using the following inclusion criteria: 1) DTC; 2) LR and IR patients; 3) non-RRA-treated patients or RRA-treated vs non-RRA-treated groups; 4) a report of the outcome of cancer recurrence; and 5) publication since 2008.Neck ultrasonography is superior to whole-body scan for disease detection in the neck. A rising or declining serum thyroglobulin level over time provides an excellent positive or negative predictive value, respectively, even in non-RRA-treated patients. No OP demonstrating RRA benefit on recurrence in LR patients was found; two OPs found no evidence of benefit. We found 11 OPs that observed some benefit in reducing recurrence rates with RRA in IR patients and 13 OPs that failed to show benefit from RRA in this group.Neck ultrasonography and serum thyroglobulin measurement are equivalent or superior in detecting and localizing residual disease compared to post-therapy whole-body scan. There is no evidence of RRA benefit in recurrence prevention for LR patients. There are conflicting data on IR patients and only a few studies with homogenous and properly stratified populations. A careful evaluation of tumor pathological features and patient characteristics and preferences should guide RRA decision making.

Background: Differentiated papillary thyroid cancer is mostly sporadic, but the recurrence of the familial form has been reported. Short or dysfunctional telomeres have been associated with familial benign diseases and familial breast cancer. Objective: The aim of our work was to study the telomere-telomerase complex in the peripheral blood of patients with familial papillary thyroid cancer (FPTC), including the measurement of relative telomere length (RTL), telomerase reverse transcriptase (hTERT) gene amplification, hTERT mRNA expression, telomerase protein activity, and search of hTERT or telomerase RNA component gene mutations. Patients: Cumulating a series of patients seen at the University of Siena and a series at the University of Rome, the experiments were conducted in 47 FPTC patients, 75 sporadic papillary thyroid cancer (PTC) patients, 20 patients with nodular goiter, 19 healthy subjects, and 20 unaffected siblings of FPTC patients. Results: RTL, measured by quantitative PCR, was significantly (P < 0.0001) shorter in the blood of FPTC patients, compared with sporadic PTCs, healthy subjects, nodular goiter subjects, and unaffected siblings. Also by fluorescence in situ hybridization analysis, the results confirmed shorter telomere lengths in FPTC patients (P = 0.01). hTERT gene amplification was significantly (P < 0.0001) higher in FPTC patients, compared with the other groups, and in particular, it was significantly (P = 0.03) greater in offspring with respect to parents. hTERT mRNA expression, as well as telomerase activity, was significantly higher (P = 0.0003 and P < 0.0001, respectively) in FPTC patients, compared with sporadic PTCs. RTL, measured in cancer tissues, was shorter (P < 0.0001) in FPTC patients, compared with sporadic PTCs. No mutations of the telomerase RNA component and hTERT genes were found. Conclusion: Our study demonstrates that patients with FPTC display an imbalance of the telomere-telomerase complex in the peripheral blood, characterized by short telomeres, hTERT gene amplification, and expression. These features may be implicated in the inherited predisposition to develop FPTC.

Context: Type 2 deiodinase (D2) converts T4 in T3 in several human tissues, including hypothalamus and pituitary, and, therefore, plays a pivotal role in the negative feedback regulation of TSH secretion. A common variant of the gene, threonine (Thr) 92 alanine (Ala), has been identified and associated with decreased D2 enzymatic activity. Objective: Our objective was to investigate whether this polymorphism predicts the T4 dosage needed to obtain target TSH levels in thyroidectomized patients. Setting: Ambulatory patients were included in the study. Patients: A total of 191 consecutive thyroid cancer patients, previously treated by near total thyroidectomy and radioiodine ablation, were studied. They were on stable T4 dose treatment aimed at obtaining either suppressed (supp) (n = 117, < 0.1 mU/liter) or near-supp (n = 74, ≥ 0.1 < 0.5 mU/liter) serum TSH levels. Main Outcome Measures: DNA genotyping for D2 Thr92Ala variant and evaluation of T4 dose (μg/kg) needed to obtain target TSH levels were determined. Results: Ala/Ala homozygous patients needed a higher T4 dose as compared with patients carrying the Thr92 variant (X/Thr patients) according to a recessive genetic model (2.08 ± 0.43 vs. 1.90 ± 0.35 μg/kg; P < 0.05). This difference was observable in the near-supp group (P = 0.002), but not in the supp group (P = 0.4). Conclusions: D2 Thr92Ala polymorphism seems to predict the need for higher T4 intake in thyroidectomized patients. If this finding is confirmed in additional studies, it may predict the T4 requirement to suppress TSH on the basis of the individual genetic background.

AIM: The goal of this study was to estimate the cumulative activity of (131)I to be administered to patients with distant metastases from thyroid carcinoma. METHODS: A total of 444 patients were treated from 1953-1994 for distant metastases from papillary and follicular thyroid carcinoma: 223 had lung metastases only, 115 had bone metastases only, 82 had both lung and bone metastases, and 24 had metastases at other sites. Treatment consisted of the administration of 3.7 GBq (100 mCi) (131)I after withdrawal of thyroid hormone treatment, every 3-9 months during the first 2 yr and then once a year until the disappearance of any metastatic uptake. Thyroxine treatment was given at suppressive doses between (131)I treatment courses. RESULTS: Negative imaging studies (negative total body (131)I scans and conventional radiographs) were attained in 43% of the 295 patients with (131)I uptake; more frequently in those who were younger, had well-differentiated tumors, and had a limited extent of disease. Most negative studies (96%) were obtained after the administration of 3.7-22 GBq (100-600 mCi). Almost half of negative studies were obtained more than 5 yr after the initiation of the treatment of metastases. Among patients who achieved a negative study, only 7% experienced a subsequent tumor recurrence. Overall survival at 10 yr after initiation of (131)I treatment was 92% in patients who achieved a negative study and 19% in those who did not. CONCLUSION: (131)I treatment is highly effective in younger patients with (131)I uptake and with small metastases. They should be treated until the disappearance of any uptake or until a cumulative activity of 22 GBq has been administered. In the other patients, other treatment modalities should be used when tumor progression has been documented.