BRAF mutation analysis in thyroid nodules with indeterminate cytology: our experience on surgical management of patients with thyroid nodules from an area of borderline iodine deficiency.

PURPOSE: Fine-needle aspiration (FNA) with cytologic evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytologic diagnosis remains indeterminate for 12-18 % of nodules. BRAF V600E mutation has been reported to show a high specificity for malignant thyroid nodules and the use of this marker to refine indeterminate FNA cytology results may be a useful diagnostic adjunctive tool in the pre-operative evaluation of thyroid nodules. The aim of this study was to estimate the prevalence of BRAF exon 15 mutation (V600E) and its clinical value as a diagnostic tool in a series of thyroid nodules with indeterminate cytology from an area of borderline iodine deficiency. SUBJECTS AND METHODS: One hundred and fifty-three thyroid samples obtained by FNA of thyroid nodules from 151 patients were subjected to the analysis of BRAF V600E mutation by direct sequencing. In the study 54 nodules with indeterminate cytology, 56 benign and 43 malignant thyroid nodules were included. RESULTS: V600E BRAF gene mutation was demonstrated in 19/43 malignant nodules, in 0/56 benign nodules and in only 1/54 indeterminate nodules that, after histology, turned out to be at a papillary thyroid carcinoma. CONCLUSIONS: The application of BRAF exon 15 analysis showed limitations when applied to discriminate thyroid nodules with indeterminate cytology if wild-type BRAF is found, and there is no role for avoiding diagnostic thyroid surgery.

Genetic markers to discriminate benign and malignant thyroid nodules with undetermined cytology in an area of borderline iodine deficiency.

BACKGROUND: Fine needle aspiration (FNA) with cytologic evaluation is the most reliable tool for malignancy prediction in thyroid nodules, but cytologic diagnosis remains undetermined for 20% of nodules. AIM: We investigated the diagnostic potential of a set of 6 marker genes to distinguish benign and malignant thyroid nodules. SUBJECTS AND METHODS: The prospective study included 153 thyroid samples obtained by FNA of thyroid nodules from 151 patients (56 benign, 43 malignant, and 54 nodules with undetermined cytology). Gene expression was evaluated by quantitative realtime PCR and statistical analysis of data was performed. All samples were analyzed for V600E BRAF mutation. RESULTS: A decrease in TTF3 and HGD1 expression was observed in malignant nodules with respect to benign ones, while an increase in PLAB expression was demonstrated in these nodules. The decision model was valid for 88 of 99 cases of benign and malignant nodules, with a total of 11 false positive or negative predictions. The obtained malignant/benign phenotype prediction was also valid for 37 of 54 cases of nodules with undetermined cytology with a total of 8 false positive and 9 false negative predictions. V600E BRAF gene mutation was demonstrated in 19/43 malignant nodules, in 0/56 benign nodules, and in 1/54 undetermined nodules. CONCLUSIONS: The expression profiles of genes (TFF3, HGD1, and PLAB) allowed a good prediction for the differentiation of benign thyroid lesions and thyroid cancer starting from cells of FNA; however, this assay showed limitations when applied to discriminate thyroid nodules with undetermined cytology.

Papillary thyroid cancer, although strongly associated with lymphocytic infiltration on histology, is only weakly predicted by serum thyroid auto-antibodies in patients with nodular thyroid diseases.

OBJECTIVE: We evaluated the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration (FNA) cytology. DESIGN: Anti-thyroid antibodies (TAb) were measured in patients with multinodular goiter (MNG) and single/isolated thyroid nodule (S/I) submitted to FNA. Thyroid lymphocytic infiltration (LI) on histology was studied in a subgroup of patients submitted to thyroidectomy; 13,021 patients were included: on cytology 622 had papillary thyroid cancer (c- PTC) and 12,399 benign thyroid nodular diseases (c-BTN). LI was evaluated in histological samples of 688 patients: 304 with PTC (h-PTC) and 384 with BTN (h-BTN). RESULTS: TAb prevalence was not different in c-BTN and c-PTC (38.7% vs 35.6%). TAb were more frequent in c-BTN than c-PTC in females with MNG (40.1% vs 32.5%, p=0.02), and in c-PTC than in c-BTN in males with S/I (31.2% vs 20.4%, p=0.02) and, although not significantly, in females younger than 30 yr (35.1% vs 30.7%). The frequency and severity of LI was significantly higher in h-PTC than h-BTN, both in MNG (82.5% vs 45.0%, p<0.001) and S/I (85.6% vs 71.0%, p<0.001), but a higher number of patients with h-PTC had negative circulating TAb, despite the presence of moderate/severe LI. CONCLUSIONS: TAb are weakly associated to PTC in males and young females, while they are more frequent in older females with BTN. The frequency and severity of LI is significantly higher in PTC than in BTN, but in cancer patients TAb are frequently negative, despite the evidence of histological thyroiditis. These data suggest that different kinds of immune response may be involved in PTC and BTN.

Elastography: new developments in ultrasound for predicting malignancy in thyroid nodules.

BACKGROUND: Elastography is a newly developed dynamic technique that uses ultrasound (US) to provide an estimation of tissue stiffness by measuring the degree of distortion under the application of an external force. US elastography has been applied to differentiate malignant from benign lesions. PATIENTS: This study included 92 consecutive patients with a single thyroid nodule who underwent surgery for compressive symptoms or suspicion of malignancy on fine needle aspiration cytology. Tissue stiffness on US elastography was scored from one (greatest elastic strain) to five (no strain). RESULTS: On US elastography: scores 1 and 2 were found in 49 cases, all benign lesions; score 3 in 13 cases, one carcinoma and 12 benign lesions; and scores 4 and 5 in 30 cases, all carcinomas. Thus, the elasticity scores 4-5 were highly predictive of malignancy (P < 0.0001), with a sensitivity of 97%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 98%. In 32 patients with an indeterminate fine needle aspiration result, the conventional US was not predictive of malignancy, while an US elastographic score of 4-5 was observed in six of seven (86%) patients with carcinoma on histology, and a score of 1-3 in all 25 patients with benign lesions. CONCLUSIONS: US elastography has great potential as an adjunctive tool for the diagnosis of thyroid cancer, especially in indeterminate nodules on cytology. Larger prospective studies are needed to confirm these results and establish the diagnostic accuracy of this new technique.

Left ventricular papillary fibroelastoma with coronary embolization.

We describe a patient who survived an acute myocardial infarction caused by coronary embolization from a left ventricular papillary fibroelastoma. The tumour, which was detected by 2-D echocardiography, was successfully excised.

Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and of treatment with L-thyroxine.

The possible association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a still debated issue. We analyzed the frequency of PTC, TSH levels and thyroid autoantibodies (TAb) in 13 738 patients (9824 untreated and 3914 under l-thyroxine, l-T(4)). Patients with nodular-HT (n=1593) had high titer of TAb and/or hypothyroidism. Patients with nodular goiter (NG) were subdivided in TAb-NG (n=8812) with undetectable TAb and TAb+NG (n=3395) with positive TAb. Among untreated patients, those with nodular-HT showed higher frequency of PTC (9.4%) compared with both TAb-NG (6.4%; P=0.002) and TAb+NG (6.5%; P=0.009) and presented also higher serum TSH (median 1.30 vs 0.71 µU/ml, P<0.001 and 0.70 µU/ml, P<0.001 respectively). Independently of clinical diagnosis, patients with high titer of TAb showed a higher frequency of PTC (9.3%) compared to patients with low titer (6.8%, P<0.001) or negative TAb (6.3%, P<0.001) and presented also higher serum TSH (median 1.16 vs 0.75 µU/ml, P<0.001 and 0.72 µU/ml, P<0.001 respectively). PTC frequency was strongly related with serum TSH (odds ratio (OR)=1.111), slightly related with anti-thyroglobulin antibodies (OR=1.001), and unrelated with anti-thyroperoxidase antibodies. In the l-T(4)-treated group, when only patients with serum TSH levels below the median value (0.90 µU/ml) were considered, no significant difference in PTC frequency was found between nodular-HT, TAb-NG and TAb+NG. In conclusion, the frequency of PTC is significantly higher in nodular-HT than in NG and is associated with increased levels of serum TSH. Treatment with l-T(4) reduces TSH levels and decreases the occurrence of clinically detectable PTC.

L-thyroxine-treated patients with nodular goiter have lower serum TSH and lower frequency of papillary thyroid cancer: results of a cross-sectional study on 27 914 patients.

The risk of papillary thyroid cancer (PTC) is related to serum TSH, and the development of thyroid autonomy by reducing TSH levels decreases the frequency of PTC in patients with nodular goiter. Our aim was to investigate the effect of L-thyroxine (LT(4)) on the frequency of PTC diagnosed by cytology in a large series of patients with nodular goiter untreated (n=20 055) or treated with L-T(4) (n=7859). L-T(4)-treated patients with respect to untreated patients presented significantly lower serum TSH (median, interquartile range: 0.30 muU/ml, 0.08-0.62 microU/ml versus 0.70 muU/ml, 0.38-1.14 muU/ml; P<0.0001) and prevalence of PTC (3.2 vs 5.1%; P<0.0001). The frequency of PTC was closely related to serum TSH, with it being lowest in patients with TSH below the normal range (<0.4 muU/ml; 189/10 059, 1.9%) and highest in patients with TSH above the normal range (>3.4 muU/ml; 21/127, 16.5%), also showing a progressive increase from the lower to the upper quartile of normal range. A significantly higher proportion of L-T(4)-treated patients (6650/7859, 84.6%) had serum TSH below the median (0.90 muU/ml) with respect to untreated patients (12,599/20,055, 62.8%; chi(2) P value <0.0001), with it being included in the range of TSH associated with a lower frequency of PTC. The relationship between serum TSH and frequency of PTC was unrelated to the type of nodularity (solitary versus multinodular) and was not age dependent. In conclusion, patients with nodular goiter, treatment with L-T(4) is responsible for the reduction of serum TSH and is associated with a decreased frequency of PTC.

Male sex, single nodularity, and young age are associated with the risk of finding a papillary thyroid cancer on fine-needle aspiration cytology in a large series of patients with nodular thyroid disease.

OBJECTIVE: To evaluate the risk of papillary thyroid carcinoma (PTC) at fine-needle aspiration (FNA) cytology in 34 120 patients. RESULTS: False positive and false negative rates of FNA cytology were 1.2 and 1.8% in comparison with the histology in 3406 nodules from 3004 patients who underwent surgery. PTC (901 cases) was more frequent in solitary nodule (SN; 446/13 549, 3.3%) than in multinodular goiter (MNG; 411/19 923, 2%, chi(2)=48.8; P<0.0001), and in males (209/6382, 3.3%) than in females (648/26 945, 2.40%, chi(2)=15.58; P<0.0001). PTC prevalence in Graves' disease (GD; 13/286, 4.5%) and Hashimoto's thyroiditis (HT; 31/508, 6.1%) was higher than in SN, this difference being significant in HT (chi(2)=8.7; P=0.003), but not in GD (chi(2)=1.6; P=0.2). Using the multiple logistic regression analysis, independent risk predictors of PTC were determined, which were younger age (odds ratio (OR)=0.97, confidence interval (CI) 0.964-0.974; P<0.0001), male gender (OR=1.44, CI 1.231-1.683; P<0.0001), and SN versus MNG (OR=0.63, CI 0.547-0.717; P<0.0001). The individual risk predictivity was highly improved by including serum TSH in the prediction model, which was measured at FNA in 11 919 patients. CONCLUSION: A cytology suspicious or indicative of PTC was associated with younger age, male gender, and solitary versus multiple nodularity. These clinical parameters, together with serum TSH, may allow formulation of an algorithm that could be usefully applied to predict the risk of PTC in individual patients when cytology does not give a diagnostic result.

Real-time elastosonography: useful tool for refining the presurgical diagnosis in thyroid nodules with indeterminate or nondiagnostic cytology.

BACKGROUND: Indeterminate and nondiagnostic patterns represent the main limitation of fine-needle aspiration (FNA) cytology of thyroid nodules, clinical and echographic features being poorly predictive of malignancy. The newly developed real-time ultrasound elastography (USE) has been previously applied to differentiate malignant from benign lesions. The aim of this study was to get further insights into the role of USE in the presurgical diagnosis of nodules with indeterminate or nondiagnostic cytology. PATIENTS: The study included 176 patients who had one (n=138) or multiple (n=38) nodules with indeterminate or nondiagnostic cytology on FNA, for whom histology was available after thyroidectomy. A total of 195 nodules (142 indeterminate, 53 nondiagnostic) were submitted to USE, and elasticity was scored as 1 (high), 2 (intermediate), or 3 (low). RESULTS: In indeterminate lesions, the score 1, describing high elasticity, was strongly predictive of benignity, being found in 102 of 111 benign nodules and in only one of 31 carcinomas (P<0.0001). By combining the scores 2 and 3, USE had a sensitivity of 96.8% and a specificity of 91.8%. In nodules with nondiagnostic cytology, score 1 was found in 39 of 45 benign nodules and in only one of eight carcinomas (P<0.0001). By combining the scores 2 and 3, USE had a sensitivity of 87.5% and a specificity of 86.7%. CONCLUSIONS: USE may represent an important tool for the diagnosis of thyroid cancer in nodules with indeterminate or nondiagnostic cytology and may prove useful in selecting patients who are candidates for surgery.

Lower levels of TSH are associated with a lower risk of papillary thyroid cancer in patients with thyroid nodular disease: thyroid autonomy may play a protective role.

Higher TSH values, even within normal ranges, have been associated with a greater risk of thyroid malignancy. The relationship between TSH and papillary thyroid cancer (PTC) has been analyzed in 10 178 patients submitted to fine needle aspiration of thyroid nodules with a cytology of PTC (n=497) or benign thyroid nodular disease (BTND, n=9681). In 942 patients, submitted to surgery (521 from BTND and 421 from PTC), the histological diagnosis confirmed an elevated specificity (99.6%) and sensitivity (98.1%) of cytology. TSH levels were significantly higher in PTC than in BTND both in the cytological and histological series and also in patients with a clinical diagnosis of multinodular goiter (MNG) and single/isolate nodule (S/I). A significant age-dependent development of thyroid autonomy (TSH <0.4 microU/ml) was observed in patients with benign thyroid disease, but not in those with PTC, diagnosed both on cytology and histology. In patients with MNG, the frequency of thyroid autonomy was higher and the risk of PTC was lower compared to those with S/I. In all patients, the presence of thyroid auto-antibodies (TAb) was associated with a significant increase of TSH. However, both in TAb positive and TAb negative patients TSH levels were significantly higher in PTC than in BTND. Our data confirm a direct relationship between TSH levels and risk of PTC in patients with nodular thyroid diseases. Thyroid autonomy conceivably protects against the risk of PTC, while thyroid autoimmunity does not play a significant role.

Clinical features of thyroid autoimmunity are associated with thyroiditis on histology and are not predictive of malignancy in 570 patients with indeterminate nodules on cytology who had a thyroidectomy.

BACKGROUND: The relationship between thyroid autoimmunity and cancer is still uncertain. PATIENTS: We approached this issue in 570 consecutive patients submitted to thyroidectomy for an indeterminate nodule on cytology. Thyroid autoimmunity was defined as positivity of circulating thyroid autoantibodies (TAb), autoimmune hypo- or hyperthyroidism, thyroid hypoechogenicity on ultrasound, and lymphocytic infiltration on histology. RESULTS: TAb were found in 122/570 (21.4%), hypoechogenicity in 115/570 (20.1%), and lymphocytic infiltration in 117/570 (20.5%) of patients. The three features of thyroid autoimmunity were highly concordant: hypoechogenicity was observed in 71/448 (15.8%) patients with negative TAb and in 44/122 (36%) with positive TAb (P < 0.0001); lymphocytic infiltration was found in 53/448 (11.8%) patients with negative TAb and in 64/122 (52.4%) with positive TAb (P < 0.0001); hypoechogenicity on ultrasound was observed in 73/453 (16.1%) patients without, and in 42/117 (35.9%) with lymphocytic infiltration (P < 0.0001). None of these parameters was associated with malignancy. TAb were found in 32/135 (23.7%) patients with carcinoma and in 90/435 (20.6%) with a benign lesion (P = NS); hypoechogenicity was observed in 26/135 (19.2%) patients with carcinoma and in 89/435 (20.4%) patients with benign lesions (P = NS); lymphocytic infiltration was present in 28/135 (20.7%) patients with carcinoma and in 89/435 (20.4%) with benign lesions (P = NS). The frequency of cancer in 11 patients with clinically overt thyroid autoimmune disease did not differ from that observed in the whole study group. CONCLUSION: In this group of patients with indeterminate thyroid nodules at cytology, clinical and pathological criteria of thyroid autoimmunity were strongly concordant and not associated with malignancy.

Combined clinical, thyroid ultrasound and cytological features help to predict thyroid malignancy in follicular and Hupsilonrthle cell thyroid lesions: results from a series of 505 consecutive patients.

OBJECTIVE: The cytological patterns of follicular and Hupsilonrthle cell nodules are included among the indeterminate results of fine-needle aspiration cytology, because distinction between benign and malignant lesion can only be made on histological criteria. The diagnostic value of atypia at cytology, clinical parameters and echographic patterns were examined to establish the risk of malignancy in 505 patients with follicular and Hupsilonrthle cell thyroid nodules at cytology. DESIGN AND PATIENTS: The study included 505 consecutive patients who had undergone thyroidectomy from the period 2002-2005. RESULTS: Histological diagnosis of malignancy was carried out in 125 of 505 (25%) patients, the follicular variant of papillary carcinoma being the most frequent histotype. Only atypia at cytology (P < 0.0001) and spot microcalcifications at ultrasound (P = 0.009) were predictive of malignancy. Male gender, normal thyroid volume, single nodularity, nodule hypoechogenicity, size and blurred margins were associated with malignancy, although not significantly. An arbitrary clinical score allowed the identification of patients with high (41%, 110 patients) and low (16%, 242 patients) risk of malignancy. Combining the clinical score with the presence of atypia at cytology we could identify 30 patients (6%) in whom the risk of malignancy was as high as 63%. CONCLUSIONS: Twenty-five per cent of patients with a cytological result of follicular and Hupsilonrthle cell thyroid lesion had a final diagnosis of malignancy. Only atypia at cytology and spot microcalcifications at thyroid ultrasound were significantly associated with malignancy. Other clinical parameters and thyroid ultrasound patterns can be used to set up a clinical score useful for predicting the individual risk of malignancy before surgery.

The newly developed three-dimensional (3D) and two-dimensional (2D) thyroid ultrasound are strongly correlated, but 2D overestimates thyroid volume in the presence of nodules.

The newly developed three-dimensional (3D) and two-dimensional (2D) thyroid ultrasound (US) were compared in assessing thyroid volume (TV) in 104 patients: 53 had an isolated thyroid nodule, 32 toxic diffuse goiter, 17 non-toxic multinodular goiter, 1 toxic multinodular goiter and 1 a toxic adenoma. A real-time Technos apparatus (Esaote SpA, Italy) with a 7,5 MHz linear transducer was used. The volume of thyroid lobes by 2D was calculated according to the ellipsoid formula. In the same session, TV by 3D US was calculated using a probe tracking system (in vivo ScanNT Esaote 3.4 MedCom. Darmasdt) and software to reconstruct 3D images, directly giving the lobe volume. There was a very good agreement between 2D and 3D, but in 94/208 lobes with nodular lesions 2D showed a 10% systematic overestimation compared to 3D, the percentage error being higher in lobes with lower volumes. A possible explanation for this result is the inadequacy of the ellipsoid formula in forecasting the correct lobe profile in the presence of nodules. This intrinsic defect of 2D US should be taken into account when evaluating TV in patients with nodular goiter.

Progress in the surgical treatment of ventricular septal defect: an analysis of a twelve years' experience.

Two hundred sixty-seven patients underwent surgical closure of a ventricular septal defect (VSD) over a 12-year period between January 1, 1970 and December 31, 1982. In 152 patients (57%) an associated lesion was present complicating the treatment of the primary lesion: 7 patients had multiple VSDs and among those with single defects, 189 were large (unrestrictive). The median age was 5.2 years ranging from 1 month to 46 years. Sixty-nine were infants under 10 kg of weight. The 30-day operative mortality was 8.6% (23 cases). The main cause of death was a low output syndrome in 16 cases. Thirty-two variables have been collected and their relationship with the death of the patients has been analyzed with univariate and multivariate methods. Logistic analysis has identified the independent significant incremental effect on hospital mortality of low weight (P greater than 0.00001), early operative date (P greater than 0.00001), multiplicity of defects (P = 0.0008), presence of major associated lesions (P = 0.019); the large size of the defect was only probably significant (P = 0.18). Inspection of the nomograms, relating the probability of operative death to weight and age in patients with a large defect, shows that the risk is significantly higher in the 3 kg baby (median age 3.3 months), particularly if major associated lesions are present. In infants with multiple VSDs the risk of operation remains, at the end of 1982, significantly higher than in single defects. However, our data suggest that the risk of open correction in patients over 12 kg of weight approaches that of single VSD if concomitant lesions do not complicate the surgical treatment.