Robert A. Wahl

Prophylactic Thyroidectomy in 75 Children and Adolescents with Hereditary Medullary Thyroid Carcinoma: German and Austrian Experience

Abstract. When mutations of theRETproto-oncogene were found in 1993 to account for hereditary medullary thyroid carcinoma (MTC), surgeons obtained the opportunity to operate on patients prophylactically (i.e., at a clinically asymptomatic stage). Whether this approach is justified, and, if so, when and to which extent surgery should be performed remained to be clarified. A questionnaire was sent to all surgical departments in Germany and Austria. All of the patients who fulfilled the following criteria were enrolled: (1) preoperatively proved RET mutation; (2) age ≤ 20 years, (3) clinically asymptomatic thyroid C cell disease; and (4) TNM classification pT0–1/pNX/pN0–1/M0. Seventy-five patients were identified, and fifteen mutations were detected in six codons. Two adolescents had unilateral pheochromocytomas as part of the multiple endocrine neoplasia II (MEN-II) syndrome. No hyperparathyroidism was noted. All patients underwent total thyroidectomy, and 57 patients went on to have lymph node dissection. Parathyroid glands were removed in 34 patients and autografted in 11. Histopathology revealed MTC in 46 patients (61%, youngest 4 years); C cell hyperplasia (CCH) only was detected in the other 29 patients. Three patients had lymph node metastases (LNMs) the youngest being age 14 years. Calcitonin levels were not useful for differentiating between CCH and MTC, but in all patients with LNMs at least the stimulated calcitonin levels were assayed. After surgery, five patients (6.7%) sustained permanent hypoparathyroidism, and one patient (1.3%) had a permanent unilateral recurrent nerve palsy. All but three patients (96%) were biochemically cured. In conclusion, prophylactic total thyroidectomy can be performed safely in experienced centers. We recommend prophylactic total thyroidectomy at age 6. Cervicocentral lymph node dissection should be included when calcitonin levels are elevated or if patients are older than 10 years. Bilateral lymph node dissection should be performed if LNMs are suspected or when patients with elevated calcitonin are older than 15 years.

German Association of Endocrine Surgeons practice guidelines for the surgical treatment of benign thyroid disease

IntroductionBenign thyroid disorders are among the most common diseases in Germany, affecting around 15 million people and leading to more than 100,000 thyroid surgeries per year. Since the first German guidelines for the surgical treatment of benign goiter were published in 1998, abundant new information has become available, significantly shifting surgical strategy towards more radical interventions. Additionally, minimally invasive techniques have been developed and gained wide usage. These circumstances demanded a revision of the guidelines.MethodsBased on a review of relevant recent guidelines from other groups and additional literature, unpublished data, and clinical experience, the German Association of Endocrine Surgeons formulated new recommendations on the surgical treatment of benign thyroid diseases. These guidelines were developed through a formal expert consensus process and in collaboration with the German societies of Nuclear Medicine, Endocrinology, Pathology, and Phoniatrics & Pedaudiology as well as two patient organizations. Consensus was achieved through several moderated conferences of surgical experts and representatives of the collaborating medical societies and patient organizations.ResultsThe revised guidelines for the surgical treatment of benign thyroid diseases include recommendations regarding the preoperative assessment necessary to determine when surgery is indicated. Recommendations regarding the extent of resection, surgical techniques, and perioperative management are also given in order to optimize patient outcomes.ConclusionsEvidence-based recommendations for the surgical treatment of benign thyroid diseases have been created to aid the surgeon and to support optimal patient care, based on current knowledge. These recommendations comply with the Association of the Scientific Medical Societies in Germany requirements for S2k guidelines.

Real-time ultrasound elastography—a noninvasive diagnostic procedure for evaluating dominant thyroid nodules

PurposeUltrasound elastography (USE) is a newly developed technique for the evaluation of tissue stiffness. It is known that malignancies often show a low-strain value. So far, only limited data for thyroid nodules is available.MethodsThis study included 309 prospective evaluated patients with dominant, nontoxic thyroid nodules. All patients were referred to surgery. USE was performed preoperatively. Three measuring groups were formed: hard (< 0.15), intermediate (0.16–0.3), and soft (> 0.31). The measurements were correlated to the final histological findings.ResultsThe strain rated from 0.01 to 0.84 (mean 0.26 ± 0.13). A total of 50 thyroid malignancies (35 papillara carcinoma, 9 medullary carcinoma, and 6 follicular carcinoma) were observed. Patients (81) were within the hard group, 35 of them (43.2%) had thyroid cancer (TC) in final histology. Out of 132 patients in the intermediate group, 15 patients had TC (11.4%). All 96 patients from the soft group showed benign histological results (NPV 100%). Seventy percent of patients with TC were within the hard group (PPV 42%). These results were highly significant (p < 0.001). Coarse calcifications and cystic nodules were not connected with reliable measurements and therefore are not suitable for USE.ConclusionUSE is a useful adjunctive tool in the workup of thyroid nodules. A low strain value needs surgical intervention, whereas a high strain value predicts a benign histology. It might substitute fine-needle aspiration cytology in the future.

Vitamin D receptor polymorphisms in differentiated thyroid carcinoma.

BACKGROUND Vitamin D receptor (VDR) expression has been shown to be upregulated in several tumors and is supposed to represent an important endogenous response to tumor progression. To investigate the role of the VDR gene and its influence on 25(OH)D(3) and 1,25(OH)(2)D(3) plasma levels in thyroid carcinoma, we analyzed four VDR polymorphisms in patients and healthy controls (HC). METHODS Patients with thyroid carcinoma (n = 172) (n = 132 for papillary and n = 40 for follicular) and HC (n = 321) were genotyped for the ApaI (rs7975232), TaqI (rs731236), BsmI (rs1544410), and FokI (rs10735810) polymorphisms within the VDR gene and correlated with 25(OH)D(3) and 1,25(OH)(2)D(3) plasma levels. RESULTS The genotypes AA of the ApaI (rs7975232) and FF of the FokI (rs10735810) polymorphisms were significantly less frequent (12.5% vs. 35.2% and 25% vs. 42.1%, respectively, both corrected p [p(c)] = 0.04) in patients with follicular thyroid cancer (FTC) than in HC. Additionally, the haplotypes, Ta (57.5% vs. 41.4%; p(c) = 0.0207), af (24.6% vs. 14.3%; p(c) = 0.0116), Tab (51.1% vs. 36.8%; p(c) = 0.0495), and Tabf (18.7% vs. 13.6%; p(c) = 0.0240) were more frequent, whereas the haplotypes AF (17.1% vs. 37.2%; p(c) = 0.0008), BF (11.4% vs. 31.9%; p(c) = 0.012), tF (7.9% vs. 25.5%; p(c) = 0.0016), and tABF (7.6% vs. 23%; p(c) = 0.0115) were less frequent in the FTC patients compared to HC. Neither genotype nor haplotype frequencies differed between patients with papillary thyroid cancer (PTC) and HC. Further, individuals with PTC and FTC had a significantly lower level of circulating 1,25(OH)(2)D(3) compared to controls. In contrast, no differences of the 25(OH)D(3) concentration between patients and HC were observed. VDR polymorphisms were not associated with 25(OH)D(3) and 1,25(OH)(2)D(3) plasma levels. CONCLUSIONS Lower circulating levels of 1,25(OH)(2)D(3) are observed in patients with differentiated thyroid carcinoma. Further, while the alleles AA and FF of the ApaI (rs7975232) and FokI (rs10735810) VDR polymorphisms and the haplotype tABF confer to protection from follicular carcinoma, the haplotype Tabf appeared to be associated with an increased FTC risk. Since this is the first report associating VDR polymorphisms with thyroid carcinoma, these findings need to be confirmed in studies with larger numbers of patients.

Differentiated Operative Strategy in Minimally invasive, Video-assisted Thyroid Surgery Results in 196 Patients

To date, experience in minimally invasive thyroid surgery has been limited to unilateral lobectomy and total thyroidectomy. There are no reports regarding selective operative strategy, guided by morphology and function, which is widely accepted in endemic goiter regions. To analyze the efficiency and outcome of tissue-preserving thyroid surgery using a minimally invasive video-assisted technique (MIVA-T), a total of 196 patients were operated on for thyroid nodules between February 1999 and October 2003. Concurrent primary hyperthyroidism was treated in 22 (11%) cases. Indications for operation were solitary, multiple unilateral, or bilateral nodules with a maximum diameter of 30 mm and a maximum lobe volume of 15 ml. Contraindications for minimally invasive operation were thyroid malignancy diagnosed by fine-needle aspiration (FNA), recurrent goiter, and Hashimotos thyroiditis. Nodule excision was performed in 6% of these cases; subtotal lobectomy, in 6%; selective resection, in 48%; and total lobectomy, in 39%. Histological examination revealed follicular adenoma in 82%, colloid and cystic lesions in 11%, thyroiditis in 1%, and differentiated thyroid carcinoma in 6%. Conversion to open surgery was necessary in 7.7% of the patients (secondary to malignancy demonstrated on frozen section in 3% and to technical difficulties in 4.7%). Transient and permanent laryngeal nerve palsy occurred in 2.0% and 0.5% of patients, respectively. Temporary hypoparathyroidism occurred in 5.6% of patients exclusively after conversion to open total thyroidectomy or in those patients ( n = 22) with additional primary hyperparathyroidism. Given a correct indication, MIVA-T technique can be performed with low conversion and complication rates. Selective operative strategy, guided by morphology and thyroid function, with a variety of operative procedures fitting the individual situation may be performed by this minimally invasive technique.To date, experience in minimally invasive thyroid surgery has been limited to unilateral lobectomy and total thyroidectomy. There are no reports regarding selective operative strategy, guided by morphology and function, which is widely accepted in endemic goiter regions. To analyze the efficiency and outcome of tissue-preserving thyroid surgery using a minimally invasive video-assisted technique (MIVA-T), a total of 196 patients were operated on for thyroid nodules between February 1999 and October 2003. Concurrent primary hyperthyroidism was treated in 22 (11%) cases. Indications for operation were solitary, multiple unilateral, or bilateral nodules with a maximum diameter of 30 mm and a maximum lobe volume of 15 ml. Contraindications for minimally invasive operation were thyroid malignancy diagnosed by fine-needle aspiration (FNA), recurrent goiter, and Hashimoto’s thyroiditis. Nodule excision was performed in 6% of these cases; subtotal lobectomy, in 6%; selective resection, in 48%; and total lobectomy, in 39%. Histological examination revealed follicular adenoma in 82%, colloid and cystic lesions in 11%, thyroiditis in 1%, and differentiated thyroid carcinoma in 6%. Conversion to open surgery was necessary in 7.7% of the patients (secondary to malignancy demonstrated on frozen section in 3% and to technical difficulties in 4.7%). Transient and permanent laryngeal nerve palsy occurred in 2.0% and 0.5% of patients, respectively. Temporary hypoparathyroidism occurred in 5.6% of patients exclusively after conversion to open total thyroidectomy or in those patients (n = 22) with additional primary hyperparathyroidism. Given a correct indication, MIVA-T technique can be performed with low conversion and complication rates. Selective operative strategy, guided by morphology and thyroid function, with a variety of operative procedures fitting the individual situation may be performed by this minimally invasive technique.

Ultrasound diagnosis of C‐cell carcinoma of the thyroid

Ultrasound screening in 9 and 21 members, respectively, of two families affected by familial C‐cell carcinoma, as well as sonographic findings in 6 patients with sporadic medullary carcinoma of the thyroid (MCT), are reported. Unilateral and bilateral tumor nodules were identified by sonography in 12 of fl total of 13 patients with MCT (n = 9) or local tumor recurrence following thyroidectomy (n = 4); one carcinoma, 3 × 6 mm in diameter, was missed. Nine of the 12 (75%) were clinically occult, nonpalpable C‐cell carcinomas. The smallest occult MCT correctly diagnosed by ultrasound had a diameter of 4 mm. A positive correlation was found between the sonographically determined tumor mass (number/size of nodules/metastases) and the plasma calcitonin level. Pheochromocytomas were diagnosed by ultrasound as part of a multiple endocrine neoplasia (MEN IIa) in two patients with MCT. The echomorphologic findings of the intrathyroid C‐cell carcinomas and their metastases display characteristic but nonspecific features. Sonographic findings on these tumors should therefore not be interpreted without consideration of plasma calcitonin assays.

Thyroid function after surgery for autonomous and non-autonomous nodular endemic goitre--effect of iodide-substitution.

SummaryThe aim of this study was to evaluate the influence of postoperative iodide-substitution on the function of thyroid remnants of different quality and quantity in order to define the appropriate prophylaxis (iodide or thyroid hormone) to prevent recurrent goitre.In a prospective, randomized clinical trial, the following patients were examined:group I: simple, non-autonomous nodular goitre, bilateral thyroidectomy (n=40);group II: simple, non-autonomous nodular goitre, “selective” (unilateral) thyroidectomy (n=40);group III: autonomous nodular goitre, bilateral thyroidectomy (n=40);group IV: autonomous nodular goitre, “selective” (unilateral) thyroidectomy (n=35). The following parameters were measured 6 and 12 weeks postoperatively. Serum-total-T4, -T3,-TSH, TRH-test, 99mTc-Thyroid-Uptake (TcTU). Six weeks postoperatively the 4 groups were separately randomized into controls and treatment groups, who received 200 µg iodide/day orally. Six weeks postoperatively, patients in group I had lower T4 levels and both basal and stimulated TSH were higher than in the other groups, however no significant differences were observed in T3, T4/T3 ratio and TcTU.Twelve weeks postoperatively patients from groups I, II and III, who had been treated with iodide, had lower T3 and TcTU values but higher T4 and T4/T3 than the appropriate controls. Basal and stimulated TSH showed no differences between controls and iodide-treated patients in these groups. In group IV, T4and T3 showed a tendency to elevation (n.s.), and basal and stimulated TSH as well as TcTU were lower in patients with iodide.Iodide-substitution (200 µg/day) has no major influence on the pituitary-thyroid axis, except after “selective” surgery for autonomous nodular goitre (group IV). Generally, iodide treatment abolishes the symptoms of iodine-deficiency, improving the autoregulatory capacity of the thyroid remnant. It could replace thyroid hormone as a prophylaxis against recurrent goitre in the majority of patients after “selective” thyroid surgery.

Low T3 syndrome in patients following major surgery.

Time sequence and specificity of thyroid hormones and biochemical parameters were investigated in patients following major surgery. Serum concentration of triiodothyronine decreases significantly following operation, with a biphasic regression. There is a reciprocal change in serum reverse triiodothyronine levels, but serum thyroxine levels show no significant change after operation. The significant decrease in serum concentration of α-2 macroglobulin and antithrombin III during and after surgery is the result of consumption of these inhibitors because the reciprocal change in serum concentration of elastase-like protease has been recognized. According to the change of curvilinear regression of serum triiodothyronine levels, 14 patients were grouped into 3. The patients for whom the curvilinear regression resembled a polynomial of degree 3 and 2 had a good prognosis, but the remaining 4 with no significant curvilinear regression had major complications and 2 died. It is meaningful that the postoperative change of triiodothyronine levels relates to the clinical outcome, to some degree.

56. Struma maligna: Symptome-Differentialdiagnostik-Operationsverfahren und Nachbehandlung

SummaryEarly and late symptoms of malignant thyroid tumors and various means of pretherapeutic diagnosis are described. Clinical suspicion can be confirmed only by surgical biopsy. The complex treatment, including surgery, radioiodine, external radiation and hormone treatment, is presented with reference to histological tumor classification. Prognosis and therapeutic results are discussed on the basis of our own experiences with 216 patients between 1955 and 1972.ZusammenfassungEinleitend werden die Friih- und Spätsymptome maligner Schilddrüsentumoren sowie die Möglichkeiten einer prütherapeutischen Diagnostik dargelegt. Sicheres Beweiskriterium im Verdachtsfall liefert allein die bioptische (histologische) Befundsicherung. Unter Berücksichtigung histologischer Tumoreigentümlichkeiten wird der komplexe Behandlungsplan (Operation, Radiojod, externe Bestrahlung, Hormone) erläutert. Aussichten der therapeutischen Bemühungen werden anhand eigener Erfahrungen bei 216 Schilddrüsencarcinom-Patienten (1955-1972) belegt.Einleitend werden die Friih- und Spatsymptome maligner Schilddrusentumoren sowie die Moglichkeiten einer prutherapeutischen Diagnostik dargelegt. Sicheres Beweiskriterium im Verdachtsfall liefert allein die bioptische (histologische) Befundsicherung. Unter Berucksichtigung histologischer Tumoreigentumlichkeiten wird der komplexe Behandlungsplan (Operation, Radiojod, externe Bestrahlung, Hormone) erlautert. Aussichten der therapeutischen Bemuhungen werden anhand eigener Erfahrungen bei 216 Schilddrusencarcinom-Patienten (1955-1972) belegt.

Chirurgie der Metastasen differenzierter Schilddrüsencarcinome

Summary84 (19.5°/x) of 431 patients with differentiated thyroid cancer developed distant metastases in bone and parenchymal organs. 78% of primary bone metastases and only 21 % of primary lung metastases were treated operatively. High survival rates of 33–60% at 5 years supported the necessity of surgical interventions primarily in bone metastases to prevent early morbidity due to pathological fractures. Even in case of questionable increase in survival rate surgery of metastases from differentiated thyroid carcinomas doubtlessly improves the quality of life in these patients.ZusammenfassungVon 431 Patienten mit differenzierten Schilddrüsencarci-nomen entwickelten 84 (19,5%) Fernmetastasen in Knochen und parenchymatösen Organen. 28 dieser 84 Patienten (33%) wurden kombiniert chirurgisch-radiologisch therapiert. Während 78% der primären Knochenmetastasen operativ behandelt wurden, traf dies nur für 21 % der primären Lungenmetastasen zu. Die hohe Fünfjahresüberlebensrate von 33–60% unterstützte die Notwendigkeit für chirurgische Interventionen speziell bei Knochmetastasen, um die drohende Morbidität aufgrund pathologischer Frakturen zu verhindern. Auch wenn in dem dargestellten Krankengut die operative Therapie keine eindeutige Lebensverlängerung bewirken konnte, war doch fraglos eine Verbesserung der Lebensqualität zu erreichen.84 (19.5%) of 431 patients with differentiated thyroid cancer developed distant metastases in bone and parenchymal organs. 78% of primary bone metastases and only 21% of primary lung metastases were treated operatively. High survival rates of 33-60% at 5 years supported the necessity of surgical interventions primarily in bone metastases to prevent early morbidity due to pathological fractures. Even in case of questionable increase in survival rate surgery of metastases from differentiated thyroid carcinomas doubtlessly improves the quality of life in these patients.