Giorgio Grani

Thyroglobulin in Lymph Node Fine-Needle Aspiration Washout: A Systematic Review and Meta-analysis of Diagnostic Accuracy

CONTEXT The thyroglobulin measurement in the needle washout after fine-needle aspiration (FNA) has been reported to increase the sensitivity of FNA in identifying lymph node (LN) metastases from differentiated thyroid cancer (DTC). OBJECTIVE The aim of the study was to estimate the diagnostic accuracy of this technique. DATA SOURCES To identify eligible studies, we searched electronic databases for original articles in English from 1975 through 2013. STUDY SELECTION Studies that enrolled participants with suspicious neck LNs during thyroid nodule workup or thyroid cancer follow-up were included. DATA EXTRACTION Working independently, authors used a standard form to extract data. For quality assessment, QUADAS2 guidelines were applied. DATA SYNTHESIS Including all the selected studies (24 studies, 2865 LNs) in the pooled analysis, overall sensitivity was 95.0% (95% confidence interval [CI], 93.7-96.0%), specificity was 94.5% (95% CI, 93.2-95.7%), and diagnostic odds ratio (DOR) was 338.91 (95% CI, 164.82-696.88) with significant heterogeneity (inconsistency [I(2)] = 65.7%; heterogeneity, P < .001). Stratifying different populations and including only patients with thyroid gland (410 LNs), pooled sensitivity was 86.2% (95% CI, 80.9-90.5%), specificity was 90.2% (85.1-94.0%), and DOR was 56.621 (22.535-142.26; I(2) = 37.3%; heterogeneity, P = .121). Including only patients after thyroidectomy (1007 LNs), pooled sensitivity was 96.9% (95% CI, 94.9-98.2%), specificity was 94.1% (91.7-96.0%), and DOR was 407.65 (198.67-836.46; I(2) = 0.0%; heterogeneity, P = .673). CONCLUSIONS Thyroglobulin measurement in washout from LN FNA has high accuracy in early detection of nodal metastases from DTC. The technique is simple, but a better standardization of criteria for patient selection, analytical methods, and cutoff levels is required.

Thyroid function in infertile patients undergoing assisted reproduction.

Thyroid disease is one of the most common endocrine conditions affecting women during reproductive age. A link between thyroid and assisted reproduction outcome is debated.

Intrinsic factors affecting adequacy of thyroid nodule fine-needle aspiration cytology.

To evaluate intrinsic nodule features predictive of an inadequate report in fine‐needle aspiration cytology (FNAC).

Ultrasonography scoring systems can rule out malignancy in cytologically indeterminate thyroid nodules

PurposeTo assess the accuracy and reproducibility of ultrasonography classification systems in characterizing cytologically indeterminate thyroid nodules.MethodsWe retrospectively identified 49 nodules that had been surgically resected owing to features classified as indeterminate according to 2010 Italian Consensus on Thyroid Cytology criteria. Three experienced sonographers independently reviewed original sonographic images of each nodule and classified it using the 2015 American Thyroid Association (ATA) guidelines and the Thyroid Imaging Reporting and Data System (TI-RADS) classification proposed by Korean radiologists; later, images were reviewed jointly to obtain consensus classifications of each nodule. Original cytology slides were similarly reviewed by three experienced cytopathologists, who reclassified the nodule (independently, then jointly) according to revised Italian Consensus on Thyroid Cytology (ICTC-2014) criteria. Consensus ICTC-2014, ATA, and TI-RADS classifications were analyzed against surgical histology reports to estimate each system’s sensitivity, specificity, positive and negative predictive values.ResultsOf the 49 indeterminate nodules examined, 30 (61.2 %) were histologically benign. Consensus ICTC-2014 classification correctly classified malignant nodules with positive predictive value of 50 % and negative predictive value of 90 %. Sonographic classification of nodules as intermediate to high suspicion by ATA or TI-RADS category 4c displayed positive predictive value of 63 and 71 %, respectively; positive predictive values dropped to 44 and 42 % when lower positivity thresholds were used (ATA low suspicion, TI-RADS category 4a). Negative predictive values for ATA and TI-RADS were 91 and 74 %, respectively, with higher positivity thresholds and 100 % for both with lower thresholds. All systems displayed appreciable inter-observer variability (Krippendorff alphas: ATA 0.36, TIRADS 0.42, ICTC-2014 0.74).ConclusionsWith stringent negativity cut-offs, American Thyroid Association and Thyroid Imaging Reporting and Data System assessment of cytologically indeterminate thyroid nodules allows high-confidence exclusion of malignancy.

Risk Stratification of Neck Lesions Detected Sonographically During the Follow-Up of Differentiated Thyroid Cancer

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 classifications 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 ETAs evidence-based classification of sonographically detected neck abnormalities can help identify papillary thyroid cancer patients eligible for more relaxed follow-up.

Follicular thyroid cancer and Hürthle cell carcinoma: challenges in diagnosis, treatment, and clinical management

Follicular thyroid cancer is the second most common differentiated thyroid cancer histological type and has been overshadowed by its more common counterpart-papillary thyroid cancer-despite its unique biological behaviour and less favourable outcomes. In this Review, we comprehensively review the literature on follicular thyroid cancer to provide an evidence-based guide to the management of these tumours, to highlight the lack of evidence behind guideline recommendations, and to identify changes and challenges over the past decades in diagnosis, prognosis, and treatment. We highlight that correct identification of cancer in indeterminate cytological samples is challenging and ultrasonographic features can be misleading. Despite certain unique aspects of follicular thyroid cancer presentation and prognosis, no specific recommendations exist for follicular thyroid cancer and Hürthle cell carcinoma in evidence-based guidelines. Efforts should be made to stimulate additional research in this field.

Therapy of hyperthyroidism in pregnancy and breastfeeding.

Uncontrolled hyperthyroidism in pregnancy is associated with an increased risk of perinatal complications. The state of the art discussed here has been derived through a wide MEDLINE search throughout English-language literature by using a combination of words such as hyperthyroidism, propylthiouracil (PTU), methimazole, rituximab, and pregnancy to identify original related works and review articles. Thioamides are the main first-line therapeutic options, whereas beta-blockers and iodine are second-choice drugs; surgery is resorted to only in exceptional cases. Methimazole and PTU reduce the production of thyroid hormones by selectively inhibiting thyroid peroxidase. PTU was once considered to be the first-choice drug in the treatment of gestational hyperthyroidism; however, the United States Food and Drug Administration now recommends it as a second-line thioamide, which should be used solely by women in their first trimester of pregnancy. Thyroidectomy is to be carried out only in pregnant women affected by life-threatening, uncontrollable hyperthyroidism, or in cases with thioamide intolerance. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After completion of this article, the physician should be better able to choose appropriate therapies for hyperthyroidism in pregnant women, assess the risk of possible complications due to maternal hyperthyroidism, and evaluate strategies for patient follow-up.

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.

Identification of Thyroid-Associated Serum microRNA Profiles and Their Potential Use in Thyroid Cancer Follow-Up

Context: Trends toward more conservative management of papillary thyroid cancer (PTC) diminish the primacy of serum thyroglobulin (Tg) assays as a posttreatment surveillance tool. Objective: To identify thyroid tumor-associated microRNAs (miRNAs) in the serum with potential for development as unique biomarkers of PTC recurrence. Methods: We measured expression of 754 miRNAs in serum samples collected from 11 patients with PTC before and 30 days after thyroidectomy. Major candidates were then re-evaluated by absolute quantitative polymerase chain reaction analysis in an independent cohort of patients with PTC (n = 44) or benign nodules and 20 healthy controls (HCs). The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy. Results: Eight miRNAs (miR-221-3p, miR-222-3p, miR-146a-5p, miR-24-3p, miR-146b-5p, miR-191-5p, miR-103a-3p, and miR-28-3p) displayed levels in prethyroidectomy serum samples from patients with PTC that significantly exceeded those measured after thyroidectomy and those found in samples from HCs. The 2 most promising candidates—miR-146a-5p and miR-221-3p —were further analyzed in the 20 PTC patients mentioned earlier. Serum levels of both miRNAs after 1 to 2 years of follow-up were consistent with ATA responses to therapy in all patients, including 2 with structural evidence of disease whose Tg assays remained negative (<1 ng/mL). Conclusion: miR-146a-5p and miR-221-3p hold remarkable promise as serum biomarkers for post-treatment monitoring of PTC patients, especially when Tg assay results are uninformative.

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