Thyroid autoimmunity and hypothyroidism are associated with deep molecular response in patients with chronic myeloid leukemia on tyrosine kinase inhibitors.

PURPOSE: Thyroid alterations including de novo appearance of thyroid autoimmunity are adverse effects of tyrosine kinase inhibitors, used in solid and hematologic cancer therapy, but the relationship between thyroid alterations during this treatment and the outcome of chronic myeloid leukemia remains unclear. Aim of this study was to investigate whether the presence of thyroid alterations may affect the clinical outcome of chronic myeloid leukemia on tyrosine kinase inhibitors. METHODS: We evaluated thyroid function and autoimmunity in 69 chronic myeloid leukemia patients on long-term therapy looking at the association between thyroid abnormalities and disease molecular response. RESULTS: Overall, 24 of 69 (34.8%) had one or more thyroid abnormalities during therapy. A high percentage of patients (21/69, 30.4%) showed thyroid autoimmunity (positive thyroid autoantibodies with ultrasound hypoechogenicity), while clinical and subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, found in 4 of 69 (5.8%) and 3 of 69 (4.3%) of cases. Second-generation tyrosine kinase inhibitors resulted significantly associated (14/32, 43.7%) with Hashimoto's thyroiditis, compared to first generation (7/37, 18.9%; p = 0.03). Interestingly, we also found a significant association between euthyroid (14/26, 53.8%) and hypothyroid Hashimoto's thyroiditis (4/26, 15.4%) in patients with deep molecular response, as compared to euthyroid (3/43, 7%; p = 0.0001) and hypothyroid (0/43, 0%; p = 0.02) Hashimoto's thyroiditis patients with major molecular response. CONCLUSIONS: Our study confirms and extends our knowledge on the tyrosine kinase inhibitors effects on thyroid, showing that thyroid autoimmunity is frequently observed in chronic myeloid leukemia patients on long-term therapy and is associated with a better oncological response.

Features and outcome of differentiated thyroid carcinoma associated with Graves' disease: results of a large, retrospective, multicenter study.

BACKGROUND: Whether differentiated thyroid cancer (DTC) occurring concomitantly with Graves' disease (GD) is more aggressive and bound to a less favorable outcome is controversial. OBJECTIVE: Aim of this multicenter retrospective study was to compare baseline features and outcome of DTC patients with GD (DTC/GD+) or without GD (DTC/GD-). PATIENTS: Enrolled in this study were 579 patients referred to five endocrine units (Cagliari, Pavia, Pisa, Siena, and Varese) between 2005 and 2014: 193 patients had DTC/GD+ , 386 DTC/GD-. Patients were matched for age, gender and tumor size. They underwent surgery because of malignancy, large goiter size, or relapse of hyperthyroidism in GD. RESULTS: Baseline DTC features (histology, lymph node metastases, extrathyroidal extension) did not differ in the two groups, except for multifocality which was significantly more frequent in DTC/GD+ (27.5% vs. 7.5%, p < 0.0001). At the end of follow-up (median 7.5 years), 86% of DTC/GD+ and 89.6% DTC/GD- patients were free of disease. Patients with persistent or recurrent disease (PRD) had "biochemical disease" in the majority of cases. Microcarcinomas were more frequent in the DTC/GD+ group (60% vs. 37%, p < 0.0001) and had an excellent outcome, with no difference in PRD between groups. However, in carcinomas ≥ 1 cm, PRD was significantly more common in DTC/GD+ (24.4% vs. 11.5%; p = 0.005). In the whole group, univariate and multivariate analyses showed that GD+ , lymph node involvement, extrathyroidal invasion, multifocality and tall cell histotype were associated with a worse outcome. Female gender and microcarcinomas were favorable features. No association was found between baseline TSH-receptor antibody levels and outcome. Graves' orbitopathy (GO) seemed to be associated with a better outcome of DTC, possibly because patients with GO may early undergo surgery for hyperthyroidism. CONCLUSIONS: GD may be associated with a worse outcome of coexisting DTC only if cancer is ≥ 1 cm, whereas clinical outcome of microcarcinomas is not related to the presence/absence of GD.

High prevalence of papillary thyroid carcinoma in nodular Hashimoto's thyroiditis at the first diagnosis and during the follow-up.

BACKGROUND: The association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) remains to be elucidated. MATERIALS AND METHODS: A total of 484 HT patients were retrospectively subdivided into two groups: 243 without thyroid nodules, TNs (HTN-) and 241 with TNs (HTN+). Fine-needle aspiration cytology was available in 152 HTN+ patients. This group was compared to a group of 161 patients with nodular goiter (NG) without HT. Finally, 70 HTN+ and 37 NG patients underwent surgery. RESULTS: A very high prevalence of suspicious/malignant cytology (Thy 4-5) at the first diagnosis (38/124; 31%) and during the follow-up (6/28; 22%) was found in HTN+ group. In HTN- group, 22/130 (17%) patients developed TN, but none showed malignant features during the follow-up. HTN+ patients had higher prevalence of Thy 4-5 (44/152 = 28.9%) compared to NG patients (12/161 = 7.4%, p < 0.0001). Increased independent odds ratio (OR) for malignancy was conferred by serum TSH > 1.0 µUI/ml, [OR 1.93, 95% confidence interval (CI) 1.41-2.64, p < 0.0001], male sex (OR 3.44, CI 1.48-8.02, p = 0.004) and HT (OR 3.14; CI 1.08-9.31, p < 0.05). Malignant histology (mostly PTC) was confirmed higher in HTN+ (48/70, 68.6%) compared to NG (15/37, 40.5%; p < 0.05). Higher prevalence of extrathyroidal infiltration (24/48, 50%) and vascular invasion (25/48, 52%) was found in HTN+ vs NG (2/15, 1.3% p < 0.01), (3/16, 1.8% p < 0.05), respectively. CONCLUSIONS: This study confirms higher prevalence of suspicious/malignant cytology and PTC at histology in nodular HT compared to NG, without evidence of malignancy in non-nodular HT patients during the follow-up.

Both thyroid autoimmunity and increased serum TSH are independent risk factors for malignancy in patients with thyroid nodules.

AIM: To assess the relevance of thyroid autoimmunity and TSH as risk factors for malignancy in thyroid nodules (TN). SUBJECTS AND METHODS: Retrospective analysis on 2053 patients with single/prevalent TN submitted to fine needle aspiration cytology (FNAC). Anti-thyroid autoantibodies (ATA) [anti-thyroperoxidase (TPOAb), anti-thyroglobulin (TgAb)] and TSH were measured. Cytology was classified as benign (class II), indeterminate (class III), and suspicious or malignant (class IV). Histology was available in 301 patients. Associations of malignancy with independent variables were determined by multivariate logistic regression analysis. RESULTS: Higher prevalence of class IV (14.2% vs 6.8%: p<0.001) and class III (23.5% vs 17.1%: p<0.001) were found in ATA+ vs ATA- TN. Histology confirmed increased prevalence of cancer in ATA+ (p<0.05) TN and in those with diffuse lymphocytic thyroid infiltration (p<0.05). Interestingly, the prevalence of malignancies observed in operated class III nodules was strikingly lower in ATA+ (1/20, 5%), than in ATA- patients (34/67, 50.7%; p<0.001). Increased independent odds ratio (OR) for malignancy was conferred by any ATA [OR 2.21; 95% confidence interval (CI)=1.49-3.29, p<0.0001]; TPOAb (OR 2.15; CI=1.42-3.25, p<0.0001) and TgAb (OR 1.67; CI=1.05-2.67, p<0.05), by serum TSH>1.0 µUI/ml (OR 1.95; CI=1.01-3.76, p<0.05), and by young age (10-29 yr: OR 2.09; CI=1.02-4.26, p<0.05). A formula was calculated to assess the relative contribution of ATA, TSH, and age to the risk of TN malignancy. CONCLUSIONS: Both thyroid autoimmunity and increased TSH represent independent risk factors for TN malignancy.

Intraoperative parathyroid hormone assay during focused parathyroidectomy for primary hyperparathyroidism: is it really mandatory?

AIM: Intraoperative parathyroid hormone (PTH) assay has become an essential tool in focused parathyroid surgery. The aim of this study was to evaluate the present role of intraoperative PTH monitoring during focused parathyroidectomy for primary hyperparathyroidism in our experience. METHODS: One hundred sixty-one patients were submitted to focused parathyroidectomy with rapid intraoperative Parathyroid hormone assay monitoring. RESULTS: A >50% decrease of PTH occurred in 147 patients (91.3%); in this group persistent hypercalcemia was found in 1; in the remaining 14 (8.7%) values of PTH decreased less than 50% and bilateral neck exploration was performed. An additional pathologic parathyroid was removed in 8 cases, a third in one; in the other five further neck exploration was negative and in four of these persistent postoperative hypercalcemia was demonstrated. In 136 patients >50% decrease of PTH was obtained after 10 minutes, in the other 11 after 20. The overall operative success of the patients was 96.9% with a 5.6% incidence of multiglandular disease. Intraoperative parathormone monitoring changed the operative management in 8.7% of cases. Intraoperative parathormone monitoring was accurate in predicting operative success or failure in 98.7% of patients, with a sensitivity of 99.3%, a specificity of 92.8%, a positive predictive value of 99.3% and a negative predictive value of 92.8%. DISCUSSION AND CONCLUSION: The measurement of intraoperative PTH represents a useful tool to assist the surgeon during parathyroid surgery and its routine use significantly improves cure rates of focused parathyroidectomy. We believe that the use intraoperative PTH is still mandatory in focused parathyroidectomy avoiding relapses and consequent reintervention.

Amiodarone-induced thyrotoxicosis. A review.

Amiodarone (AM), a potent class III anti-arrhythmic drug, is an iodine-rich compound with a structural resemblance to thyroid hormones triiodothyronine (T3) and thyroxine (T4). At the commonly employed doses, AM causes iodine overload up to 50-100 times the optimal daily intake, which may be responsible of a spectrum of effects on thyroid function often counterbalancing its heart benefits. Although most patients on chronic AM treatment remain euthyroid, a consistent proportion may develop thyrotoxicosis (AM-induced thyrotoxicosis, AIT) or hypothyroidism. AIT is more prevalent in iodine-deficient areas and is currently subdivided in two different clinico-pathological forms (AIT I and AIT II). AIT I develops in subjects with underlying thyroid disease, and is caused by an exacerbation by iodine load of thyroid autonomous function; AIT II occurs in patients with no underlying thyroid disease and is probably consequent to a drug-induced destructive thyroiditis. Mixed or indeterminate forms of AIT encompassing several features of both AIT I and AIT II may be also observed. The differential diagnosis between AIT I and AIT II (which is important for the choice of the appropriate therapy) is currently made on radioiodine uptake (RAIU), which may be high, normal or low but detectable in AIT I, while is consistently very low or undetectable in AIT II and on colour-flow Doppler sonography (CFDS) showing normal or increased vascularity in AIT I and absent vascularity in AIT II. Quite recently, studies carried out in our Units at the University of Cagliari (Italy) showed that sestaMIBI thyroid scintigraphy may represent the best single test to differentiate AIT I (showing increased MIBI retention) from AIT II (displaying no significant uptake). Treatment of AIT is dependent from its etiology. AIT usually responds to combined thionamides and potassium perchlorate (KClO4) therapy, AIT II generally responds to glucocorticoids, while indeterminate forms may require both therapeutic approaches. In patients with AIT I definitive treatment of hyperthyroidism by administration of (131)I, initially not feasible for the low RAIU and/or the risk of thyrotoxicosis exacerbation, is advised after normalization of iodine overload. To control severe AIT additional treatment with lithium carbonate, the use of short course of iopanoic acid and plasmapheresis have been also proposed. In cases resistant to medical treatment and/or in patients with severe cardiac diseases who cannot interrupt AM or require quick AM reintroduction, total thyroidectomy (possibly carried out by minimally invasive video-assisted technique) may be proposed after rapid correction of thyrotoxicosis with combination of thionamides, KClO4, corticosteroids and a short course of iopanoic acid.

The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-Tg antibodies.

OBJECTIVE: Serum thyroglobulin (Tg) is the marker of differentiated thyroid carcinoma (DTC) after total thyroidectomy, but its value is limited by the interference of anti-Tg antibodies (TgAb). Detection of Tg in fine-needle aspiration biopsy (Tg-FNAB) washout fluid is used to identify neck DTC recurrences/metastases, but the interference of serum TgAb in this procedure is unknown. PATIENTS AND METHODS: Seventy-three patients (41 after surgery for thyroid cancer and 32 with thyroid nodules) evaluated for suspicious cervical lymph nodes were retrospectively reviewed. Tg was assayed by immunoradiometric assay or chemiluminescent assay in ultrasound-guided FNAB used for cytology. Serum TgAb were detected by passive agglutination or chemiluminescent assay. On the basis of preliminary data obtained in lymphadenitis, Tg-FNAB more than 36 ng/ml and more than 1.7 ng/ml (in the presence or absence of thyroid gland, respectively) was considered as indicative of metastasis. RESULTS: In 51 TgAb-negative patients, Tg-FNAB was positive in 15 (12 with malignant and three with nondiagnostic cytology), all with histologically confirmed DTC metastases. Of the remaining 36 patients with negative Tg-FNAB, 30 had nonsuspicious and six had suspicious cytology. Histology of the latter showed four undifferentiated thyroid cancer metastases and two lymphadenitis. In 22 TgAb-positive patients, Tg-FNAB was positive in 14 (12 with malignant and two with nondiagnostic cytology), all with histologically confirmed DTC metastases. CONCLUSIONS: Clinical performance of Tg-FNAB appears to be not substantially affected by TgAb, and this procedure remains superior to cytology in the identification of DTC neck metastases. However, cytology should always be performed because, irrespective of TgAb, Tg is undetectable in FNAB from undifferentiated metastases.

High prevalence of suspicious cytology in thyroid nodules associated with positive thyroid autoantibodies.

OBJECTIVE: We assessed the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration cytology (FNAC) to avoid the selection bias of surgical series. SUBJECTS AND METHODS: Ultrasound (US)-guided FNACs were obtained from 590 unselected consecutive patients with single thyroid nodules and positive (ATA + , n = 197) or negative (ATA - , n = 393) serum anti-thyroid antibody (ATA). Cytological results were classified in three classes of increased risk of malignancy: low risk or benign (class II); indeterminate risk (class III); and suspect or malignant (class IV). RESULTS: A higher prevalence of class III (28.9% vs 21.4%, P < 0.05) and class IV (18.8% vs 9.2%, P < 0.001) and lower prevalence of class II (52.3% vs 69.5%, P < 0.001) were found in ATA + vs ATA - nodules respectively. By multivariate logistic regression analysis ATA + conferred a significant risk (odds ratio (OR): 2.29 (95% confidence interval (CI): 1.39-3.76)) for class IV cytology independently from age and sex. In 106 patients where thyroidectomy was carried out, thyroid cancer was found in 54/61 (88.5%) patients with class IV nodules (with similar positive predictive value for cancer in ATA + (96.4%) and ATA- (81.8%) nodules), in 6/31 (19.3%) of class III nodules (all ATA - ) and in none of 14 class II nodules. Non-specific cytological atypias from hyperplastic nodules in lymphocytic thyroiditis probably accounted for the different prevalence of cancer in class III ATA + and ATA - nodules. Histologically proven thyroid cancer (mostly papillary) was then observed in a higher proportion (27/197 = 13.7%) of ATA + , when compared with ATA - nodules (33/393 = 8.4%, P = 0.044), but the significance of this finding is limited by the low number of class II nodules operated on. CONCLUSIONS: The presence of ATA + confers an increased risk of suspicious or malignant cytology in unselected thyroid nodules. Since ATA + is not responsible for increased false-positive class IV FNAC, our study provides indirect evidence supporting a significant association between thyroid carcinoma and thyroid autoimmunity, although further studies with a different design are needed for a definitive histological proof.

The usefulness of 99mTc-SestaMIBI scan in the diagnostic evaluation of thyroid nodules with oncocytic cytology.

OBJECTIVE: To assess the relevance of (99m)Tc-SestaMIBI (MIBI) scan in the diagnostic evaluation of thyroid nodules with oncocytic cytology. SUBJECTS AND METHODS: Twenty-four patients with a single (or prevalent) 'cold' solid nodule with Hurthle cells (HC) at fine needle aspiration cytology (FNAC) were studied. Cytological diagnosis of oncocytic metaplasia (OM) or HC tumor (HCT) was made when HC on the smear were comprised 10-75%, or >75%. Nodules concentrating MIBI at early and late (2 h after washout) stages were considered MIBI-positive. In all cases histological findings were obtained after total thyroidectomy. RESULTS: FNAC was malignant or suspect for malignancy in 16 cases (six HCT and 10 OM) and not suspect in eight (two HCT and six OM). Histological examination revealed 14 malignant tumors (11 HCT and three OM), and 10 benign thyroid lesions (three HCT and seven OM). Sensitivity of FNAC for malignancy was 92.8% and specificity was 70.0%; HCT were identified by FNAC in only 35.7% and OM in 70.0% of cases. No significant difference in MIBI positivity was found between malignant and benign thyroid nodules. The highest percentage of MIBI positivity was found in HCT (78.5%), but MIBI-positive nodules were also observed in thyroid lesions with HC metaplasia (40.0%). CONCLUSIONS: MIBI scintiscan has no value in differentiating malignant from benign HC thyroid neoplasias. Most HCT are MIBI-positive, but this scan is not sufficiently specific to differentiate true HC neoplasias from other thyroid lesions showing HC at FNAC, although an MIBI-negative scan strongly supports the absence of true HCT.

Hypothyroid Hashimoto's thyroiditis with scintigraphic and echo-color Doppler features mimicking autonomous adenoma.

We investigated a 48-yr-old woman on L-T4 therapy (100 microg/d) for primary autoimmune hypothyroidism, diagnosed 15 yr earlier, presenting a firm oval lump in the right thyroid lobe and symptoms of mild thyrotoxicosis. Free T4, free T3, TSH, anti-thyroperoxidase, anti-TG and anti-thyroid microsomal antibodies were determined. Thyroid US and color flow Doppler sonography (CFDS), 99mTechnetium (99mTc), radioiodine scintiscan and US guided fine needle aspiration cytology (FNAC) were performed. On L-T4 therapy, thyroid function tests showed subclinical hyperthyroidism with high anti-thyroid antibody titers. Thyroid US and CFDS revealed a voluminous hypoechoic hypervascularized nodule with increased peak systolic velocity (type III pattern) in the right lobe; the extranodular tissue volume was markedly reduced and hypoechoic. The presence of an autonomous functioning nodule associated to Hashimoto's thyroiditis (HT) was suspected, L-T4 therapy was temporary withdrawn, and the patient re-evaluated 2 months later. Off L-T4 therapy, thyroid function tests revealed marked primary hypothyroidism, while thyroid US and CFDS were unchanged. 99mTc thyroid scan showed a focal increased uptake corresponding to the nodule in the right lobe with nearly absent uptake in the remaining thyroid tissue. Only a faint, patchy thyroid distribution of 131I was detected by radioiodine scan, and RAIU was very low. Cytological examination by FNAC revealed normal follicular cells and several lymphocytes. The final diagnosis was therefore hypothyroid HT with pseudo-nodular thyroid tissue of the right lobe. To our knowledge, this is the first report of HT mimicking both scintigraphic and CFDS features of an autonomous functioning nodule.

The usefulness of conventional and echo colour Doppler sonography in the differential diagnosis of toxic multinodular goitres.

OBJECTIVE: To assess the potential role of conventional sonography and colour flow Doppler (CFD) sonography (CFDS) in the differential diagnosis of toxic multinodular goitres. SUBJECTS AND METHODS: We investigated 55 patients with untreated hyperthyroidism (24 with typical toxic diffuse goitre of Graves' disease (Group A); 26 with multinodular goitre (Group B); and five with single toxic adenoma (Group C); 22 euthyroid subjects (12 with non-toxic multinodular goitre (Group D) and ten normal subjects (Group E)) were included as controls. In all cases free thyroxine, free tri-iodothyronine, TSH, TSH receptor antibodies (TRAb), anti-thyroperoxidase antibody, anti-thyroglobulin antibodies and anti-thyroid microsomal antibodies were determined and a [(99m)Tc]pertechnetate thyroid scan was performed. RESULTS: Patients with toxic multinodular goitre displayed two different CFDS patterns: 18 patients (Group B-1) had nodules with normal vascularity surrounded by diffuse parenchymal hypoechogenicity with markedly increased CFD signal and maximal peak systolic velocity (PSV) (a pattern similar to Group A patients with Graves' disease); eight patients (Group B-2) had increased intra- and perinodular CFD signal and PSV with normal extranodular vascularity (a pattern similar to that found in Group C patients with single toxic adenoma). Patients of Group B-1 showed a proportion of clinically evident thyroid ophthalmopathy, positive TRAb and other thyroid autoantibodies similar to that observed in Group A patients, while no evidence of thyroid autoimmunity was found in Group B-2. Sixteen out of 18 (89%) patients from Group B-1 displayed a scintiscan pattern of diffuse uneven radionuclide distribution, while seven out of eight (87.5%) of those from Group B-2 had localized uptake in multiple discrete nodules. Taken together, these data strongly suggest that Group B-1 mostly represents patients with the multinodular variant of Graves' disease, while Group B-2 represents patients with non-autoimmune toxic multinodular goitre. CONCLUSIONS: This study shows that combined conventional sonography and CFDS may easily distinguish nodular variants of Graves' disease from non-autoimmune forms of toxic multinodular goitre and confirms the clinical usefulness of this technique in the first-line evaluation of hyperthyroid patients.