Malignancy rates in thyroid nodules: a long-term cohort study of 17,592 patients.

Objectives: Ultrasound diagnosis of thyroid nodules has greatly increased their detection rate. Their risk for malignancy is estimated between 7 and 15% in data from specialized centers which are used for guidelines recommendations. This high rate causes considerable anxiety to patients upon first diagnosis. Here, we retrospectively analyzed the malignancy rate of sonographically diagnosed nodules larger than 1 cm from a primary/secondary care center when long-term longitudinal follow-up was included. Patients/methods: In the study, 17,592 patients were diagnosed with a thyroid nodule larger than 1 cm, of whom 7776 were assessed by fine-needle aspiration cytology (FNAC) and 9816 by sonography alone. 9568 patients were initially discharged due to innocent results of FNAC and/or ultrasound. In 1904 patients, definitive histology was obtained, and 6731 cases were included in the long-term follow-up (up to 23 years, median 5 years). Results: Malignancy was histologically confirmed in 189 patients (1.1% of all) when excluding accidentally diagnosed papillary microcarcinomas. 155 were diagnosed during the first year of management, 25 in years 2-5 of follow-up, 9 in years 6-10 and nil in 1165 patients followed beyond 10 years. Conclusions: The malignancy rate of thyroid nodules from primary/secondary care was much lower than that previously reported. During follow-up for more than 5 years, their rate rapidly dropped to less than 1/1000 cases. This low malignancy rate may help to reassure patients first confronted with the diagnosis of a thyroid nodule, substantially reduce their anxiety and avoid unwarranted diagnostic and therapeutic procedures.

Reduction of thyroid nodule volume by levothyroxine and iodine alone and in combination: a randomized, placebo-controlled trial.

CONTEXT: Nodular goiter is common worldwide, but there is still debate over the medical treatment. OBJECTIVE: The objective of the study was the measurement of the effect of a treatment with (nonsuppressive) T(4), iodine, or a combination of both compared with placebo on volume of thyroid nodules and thyroid. DESIGN: This was a multicenter, randomized, double-blind trial in patients with nodular goiter in Germany [LISA (Levothyroxin und Iodid in der Strumatherapie Als Mono-oder Kombinationstherapie) trial]. SETTING: The study was conducted in outpatient clinics in university hospitals and regional hospitals and private practices. PARTICIPANTS: One thousand twenty-four consecutively screened and centrally randomized euthyroid patients aged 18-65 yr with one or more thyroid nodules (minimal diameter 10 mm) participated in the study. INTERVENTION: Intervention included placebo, iodine (I), T(4), or T(4)+I for 1 yr. T(4) doses were adapted for a TSH target range of 0.2-0.8 mU/liter. OUTCOME MEASURES: The primary end point was percent volume reduction of all nodules measured by ultrasound, and the main secondary end point was a change in goiter volume. RESULTS: Nodule volume reductions were -17.3% [95% confidence interval (CI) -24.8/-9.0%, P < 0.001] in the T(4)+I group, -7.3% (95% CI -15.0/+1.2%, P = 0.201) in the T(4) group, and -4.0% (95% CI -11.4/+4.2%, P = 0.328) in the I group as compared with placebo. In direct comparison, the T(4)+I therapy was significantly superior to T(4) (P = 0.018) or I (P = 0.003). Thyroid volume reductions were -7.9% (95% CI -11.8/-3.9%, P < 0.001), -5.2% (95% CI -8.7/-1.6%, P = 0.024) and -2.5% (95% CI -6.2/+1.4%, P = 0.207), respectively. The T(4)+I therapy was significantly superior to I (P = 0.034) but not to T(4) (P = 0.190). CONCLUSION: In a region with a sufficient iodine supply, a 1-yr therapy with a combination of I and T(4) with incomplete suppression of thyrotropin reduced thyroid nodule volume further than either component alone or placebo.

Age and sex as predictors of biochemical activity in acromegaly: analysis of 1485 patients from the German Acromegaly Register.

OBJECTIVE: We evaluated the German Acromegaly Register for clinical variables associated with the initial biochemical activity of patients with acromegaly. DESIGN: Retrospective analysis of data in the registry. PATIENTS: A total of 1485 patients with acromegaly (males 45.6%, females 54.4%) were treated in 42 German endocrine centres until November 2005. Linear regression models were used to estimate the influence of various parameters on biochemical activity. RESULTS: Male patients with acromegaly were significantly younger at the time of diagnosis than female patients (41 vs. 47 years, P < 0.0001) and had significantly higher random GH levels than females (21 vs. 14 ng/ml, P < 0.005) and IGF-1 levels (773 vs. 679 ng/ml, P < 0.0001), respectively. Age at initial presentation turned out to be the most important independent risk factor associated with random GH levels, oral glucose tolerance test-suppressed GH levels, IGF-1 levels, body mass index (BMI), tumour size and prevalence of hypopituitarism. Sex was an independent risk factor for IGF-1 levels, BMI and prevalence of hypopituitarism. Tumour size was an independent risk factor for both GH and IGF-1 levels. CONCLUSIONS: In summary, initial biochemical activity of acromegaly is influenced by patient's age and to a lesser degree by patient's sex. Male patients are on an average 6 years younger than females.

Calcitonin measurement to detect medullary thyroid carcinoma in nodular goiter: German evidence-based consensus recommendation.

Serum calcitonin (CT) has become a very specific and sensitive marker for human medullary thyroid carcinoma (MTC), a neuroendocrine tumor affecting about 1 % of patients with nodular thyroid disease. MTC is characterized by early micrometastasis and a lack of curative non-surgical treatment, so that early diagnosis is desirable. Based on a systematic review of scientific evidence, we propose multidisciplinary consensus recommendations for the clinical use of CT in patients with nodular goiter. To exclude MTC, serum CT should be determined in patients with nodular thyroid disease, using a two-site CT immunoassay. If basal serum CT exceeds 10 pg/ml, CT should be analysed by pentagastrin stimulation testing, after renal insufficiency and proton pump inhibitor medication have been ruled out. As the risk for MTC is higher than 50 % in patients with stimulated CT values > 100 pg/ml, thyroidectomy is advised in these individuals. If stimulated CT exceeds 200 pg/ml, thyroidectomy and lymphadenectomy is strongly recommended. Pentagastrin-stimulated CT values < 100 pg/ml are associated with a low risk of MTC, or very rarely, non-metastasizing micro-MTC (size < 10 mm). Therefore, regular clinical and biochemical follow-up is the preferred treatment in such patients, unless thyroid malignancy is suspected otherwise.

A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A.

One hundred and eighty-one families with multiple endocrine neoplasia type 2A (MEN-2A) or familial medullary thyroid carcinoma (FMTC) have been investigated for mutations in the ret protooncogene in Germany. In 8 families with FMTC or MEN-2A, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11 of the ret protooncogene. DNA sequencing of additional exons (no. 13-15) revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and 11 patients with apparently sporadic tumors. Two different mutations in codon 790 (TTG-->TTT, TTG-->TTC; Leu790Phe) and one mutation in codon 791 (TAT-->TTT; Tyr791Phe) created a phenylalanine residue. We conclude that codons 790 and 791 of the ret protooncogene represent a new hot spot for FMTC/MEN-2A causing mutations. With the discovery of these considerably common mutations in codons 790 and 791 and the identification of some rare mutations, 100% of the German FMTC/MEN-2A families could be characterized by a mutation in the ret protooncogene.

[Therapy of euthyroid iron deficiency goiter. Effectiveness of a combination of L-thyroxine and 150 micrograms iodine in comparison with mono-L-thyroxine]. / Therapie der euthyreoten Jodmangelstruma. Wirksamkeit der Kombination aus L-Thyroxin und 150 micrograms Jodid im Vergleich zu Mono-L-Thyroxin.

BACKGROUND: In terms of the pathomechanism, TSH and intrathyroid iodine deficiency are the interconnecting elements between alimentary iodine deficiency and the growth and genesis of goiter. L-Thyroxine treatment for suppression of hypophyseal TSH production and supplementary iodide have a synergistic effect in reducing the size of goiter. An individual adaptation of the L-Thyroxine dose is necessary for optimal TSH suppression. Excessive suppression of the TSH level prevents uptake of iodine by the thyroid and thus compensation of the intrathyroid iodine deficiency. Combination therapy of an individually adjusted amount of L-Thyroxine with a small, mostly constant amount of iodine is a recognized concept of goiter therapy today. Administration of a combination preparation with an individually adjustable dose of L-Thyroxine and 150 micrograms iodine complies with these recommendations and improves compliance since only one tablet is required. PATIENTS AND METHODS: In the present study, the thyroid iodine supply, efficacy and tolerance of such a combination preparation was tested for the first time in 49 patients with euthyroid iodine deficiency goiter (group A). 45 patients receiving an individual L-Thyroxine therapy served as controls (group B). RESULTS: Supplementation of individually dosable L-Thyroxine with 150 micrograms iodide leads to a markedly raised iodine excretion in the urine (p < 0.005). This is an indirect indication of an improved thyroid iodine supply. Patients of group A showed a greater reduction of the thyroid volume (18.5% as compared to 16.8%, p = n. s.) and a more persistent TSH suppression (lowering by 39% [group A] as compared to a rise of 17% [group B]) in relation to the initial value (p < 0.004). This is attributable to the improved supply of iodine. CONCLUSION: The combination therapy tested was tolerated just as well as the mono-L-Thyroxine treatment with better efficacy.

Surgical reintervention for differentiated thyroid cancer.

Reoperation was performed in 110 of 185 patients with a differentiated thyroid carcinoma. In 25 patients (23 per cent) the indication for reintervention was a large thyroid remnant and in the other 85 (77 per cent) persistent or recurrent cancer was suspected. In 32 (29 per cent) of the 110 patients undergoing reoperation no evidence of cancer tissue was found. Tumour tissue in 33 patients (30 per cent) was resectable. Of 45 patients (41 per cent) with residual tumour after operation 24 showed only occult thyroid carcinoma with a raised serum thyroglobulin level. Eight of 21 patients with macroscopically persistent tumour died from the disease during a mean follow-up of 2.3 years. In 13 of 38 patients the investigated recurrent tumours were histologically less differentiated than the primary lesions, stressing the importance of total tumour clearance. The treatment of choice for persistent and recurrent differentiated thyroid carcinoma is surgical reintervention, if feasible, before radioiodine and radiation therapy are considered.

Is soluble CD25 antigen (interleukin-2 receptor) a useful parameter for differential diagnosis of thyrotoxicosis?

Soluble CD25 antigen was measured in 28 patients with Graves' disease and 20 patients with thyroid autonomy in order to address the question of whether this parameter could be used in the differential diagnosis of thyrotoxicosis. Soluble CD25 was significantly elevated in active Graves' disease (2430 +/- 442 U/ml, mean +/- SEM) compared to patients with thyroid autonomy (1295 +/- 225 U/ml, mean +/- SEM). However, compared to normal controls (mean 605 +/- 49 U/ml), both groups of patients had significantly elevated CD25 plasma levels. Investigations in thyroidectomized thyroid cancer patients on and off T4 suppressive therapy showed no influence of T4 on the CD25 level. Soluble CD25 concentrations did not differ in thyroid cancer patients compared to normal controls. We conclude that soluble CD25 may indicate a stimulation of the immune system with high sensitivity; however, due to the low specificity of elevated CD25 levels, its usefulness for differential diagnosis of thyrotoxicosis is limited.

The influence of surgery on endocrine ophthalmopathy.

Since the pathogenesis of endocrine ophthalmopathy is unclear, there has been little agreement on the treatment of the disease. The influence of thyroid surgery on endocrine ophthalmopathy is controversial. To evaluate the effect of thyroid surgery on the course of the disease, we developed a special ophthalmopathy index. As a standard procedure, subtotal thyroidectomy with thyroid remnants of 3-5 g was performed. A total of 176 patients with Graves' disease underwent the above treatment between 1986 and 1988. In 78 patients suffering from concomitant endocrine ophthalmopathy, ocular status was examined prior to operation and postoperatively. The history of endocrine ophthalmopathy had been present less than 2 years preoperatively in 74% of the patients. Follow-up ranged from 6 to 36 months. Postoperatively, 54 (69%) patients showed a marked improvement of their eye symptoms. In 18 (23%), there was no change and, in 6 (8%) patients, the severity of the eye symptoms increased after the operation. As a result of these data, a cautious and preliminary conclusion may be justified--that subtotal thyroidectomy may have a positive effect on endocrine ophthalmopathy.

[Subtotal thyroid gland resection as therapy for thyrotoxic crises]. / Subtotale Schilddrüsenresektion als Therapiekonzept bei thyreotoxischer Krise.

Thyrotoxic crises occurred in six patients (four women aged 51, 63, 72 and 76 years; two men aged 52 and 63 years). In four patients the crisis was triggered by a contrast medium containing iodine, and in one by amiodarone. The cause of the crisis in the 51-year-old woman remained uncertain. After a latent period of up to two months, T3 and T4 concentrations rose in all the patients, and abnormal findings such as tachycardia, increased blood pressure, dehydration, tremor, restlessness, hallucinations and coma ensued. Because of ineffective conservative treatment, five patients underwent subtotal thyroidectomy. In all five the symptoms and signs of hyperthyroidism were promptly relieved, and the postoperative course was uneventful. The 76-year-old woman was considered unfit for surgery because of her cardiac condition, and she died of left ventricular failure resistant to therapy.

Intestinal motor activity in experimental hyperthyroidism in conscious dogs.

The small intestinal motor effects of experimental hyperthyroidism were studied in 8 conscious dogs to reveal possible mechanisms of accelerated small bowel transit in hyperthyroidism. Six strain gauge transducers were implanted on the small intestine of each dog. Long-term hyperthyroidism was induced by subcutaneous administration of 100 and 200 micrograms/kg.day of thyroxin. Application of thyroxin did not interrupt the cyclic fasting motor activity. Thyroxin (100 micrograms/kg.day) caused a slight increase in the period of the migrating motor complex (p less than 0.05). The maximum contractile frequency rose dose-dependently up to 11% (p less than 0.05). During phase 2 and the digestive state the contraction frequency increased up to 29% and 27%, respectively (p less than 0.05). More contractions occurred in groups during the digestive state in hyperthyroidism. Half of the dogs showed giant migrating contractions during thyroxin administration, whereas those contractions were not observed during the control period. We conclude that fasted and postprandial intestinal motility is changed in experimental hyperthyroidism. Acceleration of small bowel transit may be caused by changes in contractile pattern of phase 2 and the digestive state or by the increased frequency of giant migrating contractions.

[Various strategies in the diagnosis and therapy of thyroid gland cancer. Results of a survey]. / Unterschiedliche Strategien in Diagnostik und Therapie des Schilddrüsencarcinoms. Ergebnis einer Umfrage.

In a questionnaire we compared generally adviced therapeutical and technical procedures in patients with thyroid carcinomas with the actually favorized strategy of the clinically active surgeons. At present, sonography and cytology are not favored as preoperative diagnostic tools by the questioned surgeons. Hemithyreoidectomy as primary procedure in suspicious nodules is performed only seldomly. In the treatment of thyroid carcinoma total thyroidectomy is the accepted procedure and the possibility of restricted radicality in the treatment of papillary thyroid carcinomas has gained wide acknowledgement. Most surgeons prefer to visualize the recurrent nerve and at least one or two parathyroid glands. Autotransplantation of parathyroid glands with insufficient blood supply is considered only seldomly.

Iodothyronine deiodination in rats with severe non-thyroidal illness.

To investigate the iodothyronine metabolism in non-thyroidal illness (NTI), thyroidectomized male Wistar rats bearing the hypercalcemic Walker sarcoma 256 were substituted with, respectively, 2.3 and 11.5 mumol T4/100 g body weight by daily ip injection. Serum T4 and T3 concentrations of euthyroid and hyperthyroid tumor-bearing animals markedly decreased to a nadir at day 8 after tumor implantation: serum T4 fell to, respectively, 43% (euthyroid) and 26% (hyperthyroid) of initial values, serum T3 to 19% (euthyroid) and 26% (hyperthyroid). A measurable serum rT3 concentration could not be detected before and after tumor implantation. In vitro deiodination of T4 to T3 in liver homogenates of the sacrificed animals was not significantly reduced in Walker rats compared with control animals. The activity of T4 deiodinase was significantly induced in hyperthyroid controls (180%) as well as in hyperthyroid Walker rats (155%) in spite of low serum concentrations of T4 and T3. This enzyme induction was even more pronounced in animals whose treatment with high T4 doses was started after tumor implantation. In these rats the serum concentrations of free fatty acids were increased to about 200% of controls. Our data suggest that 1. the fluctuations of iodothyronine serum concentrations in NTI are mainly independent of thyroidal secretion, and 2. the intracellular iodothyronine levels in livers of severely sick animals with different thyroid function are not greatly altered by NTI, in spite of markedly decreased total serum levels.

[Subtotal thyroidectomy as a superior therapeutic principle in the treatment of endocrine ophthalmopathy: a comparison with retrobulbar irradiation and thyrostatic therapy alone]. / Subtotale Thyreoidektomie als überlegenes Therapieprinzip bei der Behandlung der endokrinen Ophthalmopathie: Ein Vergleich mit Retrobulbärbestrahlung bzw. alleiniger thyreostatischer Therapie.

In order to investigate the influence of near total thyroidectomy on the course of endocrine ophthalmopathy (E.O.) in patients with Graves' disease, 29 patients with goitre and E.O. were classified before and after (up to 18 months) operation by use of a special ophthalmopathy index. 14 patients without goitre served as controls; they get only antithyroid drug treatment (ADT) (E.O. I and II, n = 7) or additional retoorbital irradiation (E.O. III and IV, n = 7, linear accelerator, 20 Gray). 20 out of 29 operated patients showed an improvement in the E.O., 4 a deterioration, 5 were unchanged. 3 out of 7 not operated patients with mild E.O. showed an amelioration during ADT, 4 no change. Additional radiotherapy in 7 patients with severe E.O. caused an improvement in the clinical condition of 3 patients, 3 patients deteriorated and 1 patient showed no change. It is concluded that adequate near total thyroidectomy has a positive effect on the clinical course of E.O. in patients with Graves' disease and E.O.