Jean-Louis Kraimps

Influence of Experience on Performance of Individual Surgeons in Thyroid Surgery: Prospective Cross Sectional Multicentre Study

Objective To determine the association between surgeons’ experience and postoperative complications in thyroid surgery. Design Prospective cross sectional multicentre study. Setting High volume referral centres in five academic hospitals in France. Participants All patients who underwent a thyroidectomy undertaken by every surgeon in these hospitals from 1 April 2008 to 31 December 2009. Main outcome measures Presence of two permanent major complications (recurrent laryngeal nerve palsy or hypoparathyroidism), six months after thyroid surgery. We used mixed effects logistic regression to determine the association between length of experience and postoperative complications. Results 28 surgeons completed 3574 thyroid procedures during a one year period. Overall rates of recurrent laryngeal nerve palsy and hypoparathyroidism were 2.08% (95% confidence interval 1.53% to 2.67%) and 2.69% (2.10% to 3.31%), respectively. In a multivariate analysis, 20 years or more of practice was associated with increased probability of both recurrent laryngeal nerve palsy (odds ratio 3.06 (1.07 to 8.80), P=0.04) and hypoparathyroidism (7.56 (1.79 to 31.99), P=0.01). Surgeons’ performance had a concave association with their length of experience (P=0.036) and age (P=0.035); surgeons aged 35 to 50 years had better outcomes than their younger and older colleagues. Conclusions Optimum individual performance in thyroid surgery cannot be passively achieved or maintained by accumulating experience. Factors contributing to poor performance in very experienced surgeons should be explored further.

Comprehensive Re-Sequencing of Adrenal Aldosterone Producing Lesions Reveal Three Somatic Mutations near the KCNJ5 Potassium Channel Selectivity Filter

Background Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and Methods The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. Results G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p<0.005) and their APAs with KCNJ5 mutations were larger than those without (27.1 mm vs. 17.1 mm; p<0.005). Discussion Either of two somatic KCNJ5 mutations are highly prevalent and specific for aldosterone producing lesions. These findings provide new insight into the pathogenesis of primary aldosteronism.

Primary Hyperparathyroidism in Multiple Endocrine Neoplasia Type IIa: Retrospective French Multicentric Study

Abstract. Primary hyperparathyroidism (PHPT) in multiple endocrine neoplasia (MEN) type IIa is rare, occurring in 20% to 30% of the patients. The aim of this study was to evaluate clinical findings, surgical therapy, and outcome for 56 patients affected by PHPT among 249 MEN-IIa patients collected from 84 families assembled by the Groupe d’Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group). This retrospective study was based on cases registered by the GETC (20 participating centers) from 1969 to 1994. Characteristics of PHPT in 56 patients (31 women, 25 men) with MEN-IIa were reviewed. All but two underwent cervicotomy. The median age at diagnosis was 37.6 years. PHPT was found concomitantly with medullary thyroid carcinoma (MTC) or pheochromocytoma in 43 patients (77%). PHPT was asymptomatic in 68% of the patients. Serum calcium levels ranged from 2.20 to 3.70 mmol/L (median 2.82 mmol/L; normal 2.10–2.60 mmol/L). The number of parathyroid glands removed at surgery was 0 (n = 2), 1 (n = 24), 2 (n = 5), > 2 (n = 12), 4 (n = 11). Pathology (initial surgery) consisted of 24 adenomas, 4 double adenomas, and 25 hyperplasia. Cure after initial surgery was obtained in 89%, including a 22% incidence of hypoparathyroidism. There were 6 cases (11%) with persistent PHPT. With a mean follow-up of 6.4 years, five patients (9%) had recurrent PHPT. The results indicate that MEN-IIa-related PHPT is generally associated with mild, often asymptomatic hypercalcemia. Despite recurrences encountered 5 to 15 years after the first cervicotomy, resection of only macroscopically enlarged glands generally appears sufficient. Subtotal or total parathyroidectomy with autotransplantation is associated with a high rate of hypoparathyroidism.

Risk Factors for Recurrent Nodular Goiter after Thyroidectomy for Benign Disease: Case-control Study of 244 Patients

Surgery for recurrent nodular goiter is associated with a significant risk of parathyroid and recurrent laryngeal nerve (RLN) morbidity. Total thyroidectomy for benign disease is assessed. The aim of this study was to evaluate the risk factors for recurrence and the morbidity associated with reoperation. From 1969 to 1996 a total of 4334 thyroidectomies were performed, of which 122 were for recurrent nodular goiter (group I: 116 women, 6 men). A matched case-control study of 122 patients operated on for nonrecurrent multinodular goiter was performed (group II: 112 women, 10 men). Age, family history, initial surgery, pathology, and morbidity were compared in the two groups by ċ2 test, Fisher’s exact test, and the Mantel-Haenszel test. The mean age was 39.88 years in group I and 47.89 years in group II. There was no statistical difference in relation to the extent of thyroidectomy or morbidity after initial surgery. Statistical differences were identified regarding age (p = 0.000002) and the multinodular nature of the initial goiter (p = 0.005). Bilaterality and family history were less significant (p = 0.09 and p = 0.08, respectively). Temporary RLN palsy and temporary hypoparathyroidism were higher in group I (12.3% vs. 5.7%, p = 0.0737; 10.6% vs. 1.7%, p = 0.00337). Permanent RLN palsy was found in 0.8% in group I and in none in group II (p = 0.5, NS). Young age and multiple nodules at initial surgery are risk factors for recurrence. A higher rate of temporary morbidity was demonstrated after surgery for recurrent goiter. Total thyroidectomy for multinodular goiter is advisable.

Adrenalectomy for solid tumor metastases: Results of a multicenter European study

BACKGROUND We assessed the results of adrenalectomy for solid tumor metastases in 317 patients recruited from 30 European centers. METHODS Patients with histologically proven adrenal metastatic disease and undergoing complete removal(s) of the affected gland(s) were eligible. RESULTS Non-small cell lung cancer (NSCLC) was the most frequent tumor type followed by colorectal and renal cell carcinoma. Adrenal metastases were synchronous (≤6 months) in 73 (23%) patients and isolated in 213 (67%). The median disease-free interval was 18.5 months. Laparoscopic resection was used in 46% of patients. Surgery was limited to the adrenal gland in 73% of patients and R0 resection was achieved in 86% of cases. The median overall survival was 29 months (95% confidence interval, 24.69-33.30). The survival rates at 1, 2, 3, and 5 years were 80%, 61%, 42%, and 35%, respectively. Patients with renal cancer showed a median survival of 84 months, patients with NSCLC 26 months, and patients with colorectal cancer 29 months (P = .017). Differences in survival between metachronous and synchronous lesions were also significant (30 vs. 23 months; P = .038). CONCLUSION Surgical removal of adrenal metastasis is associated with long-term survival in selected patients.

Increased calcitonin level in thyroid nodules without medullary carcinoma.

Basal calcitonin measurement is routinely performed in patients with a thyroid nodule to detect medullary carcinoma. However, increased calcitonin does not always correlate with medullary carcinoma. The aim of this study was to analyse increased calcitonin levels in patients without medullary carcinoma and to find out whether absence of this carcinoma can be predicted with certainty.

Immunohistochemical detection, regulation and antiproliferative function of G-protein-coupled receptor kinase 2 in thyroid carcinomas

TSH, via its G-protein-coupled receptor, activates cell growth of both benign and malignant thyroid tumors. G-protein-coupled receptors (GR) kinase 2 (GRK2) has been reported to regulate the TSH receptor but its role in cancer is unknown. To determine a possible function for GRK2 in the growth process of thyroid cancers, we analysed its expression in normal and tumoral thyroid tissues and studied thyroid cancer cell line proliferation after GRK2 overexpression. Thirty one thyroid tissues, including 16 non-medullary thyroid cancers and 15 adjacent normal tissues, were analysed by immunohistochemistry. Five paired tissues were also studied by western blotting for the GRK2 enzymatic activity. Immunohistochemical staining showed an increase in GRK2 in thyroid cancers including papillary, follicular, and anaplastic types, compared with their adjacent normal tissues. Immunoblot analysis and GRK2 enzymatic activity measurement confirmed immunohistochemical study. TSH and TSH in association with insulin or IGF-I stimulated GRK2 protein accumulation in normal human thyroid cells in primary culture. The TSH effect on the GRK2 expression was mimicked by forskolin. After GRK2 overexpression in two poorly differentiated thyroid cell lines, all the clones showed a significant reduction in cell proliferation, ranging from 28 to 65% inhibition compared with vector alone after 96-h culture. In conclusion, thyroid mitogenic factor-stimulated GRK2 accumulation may explain, in part, high GRK2 levels in differentiated carcinoma, because TSH, insulin, or IGF-I is known to be involved in the thyroid cancer progression. Surprisingly, instead of stimulating, GRK2 reduced cell proliferation revealing a new role for this kinase in the growth of thyroid cancers.

Histology of familial thyroid tumours linked to a gene mapping to chromosome 19p13.2

This paper describes the pathology of thyroid tumours showing an autosomal mode of inheritance linked to a gene that maps to chromosome 19p13.2. All the affected members from the family (seven males and two females; mean age 23 years) were clinically euthyroid and presented with nodular goitre; tumour recurrence after thyroidectomy was observed in four. In four of the five patients studied, the tumours were multifocal, bilateral well demarcated or encapsulated and composed of follicles, papillae, trabeculae/solid areas (often resembling hyalinizing trabecular adenoma of the thyroid) or an admixture, formed by cells with pale to intense cytoplasmic eosinophilia. A diagnosis of multiple adenomatous goitre was made in the thyroidectomy specimen from two patients, while the other two patients showed, in addition to multiple adenomas, a co‐existent oxyphil papillary carcinoma. The fifth patient had an oxyphil cell carcinoma. All tumours were of follicular cell origin as shown by immunocytochemistry. Less than a third of the benign tumours and all three carcinomas showed a variable number of neoplastic cells diffusely immunostained for mitochondria. Histological findings of a ‘multiple adenomatous goitre’, non‐endemic ‘multinodular goitre’ or multiple neoplasms of follicular cell origin with the morphology of those described here, particularly in young patients, should alert the pathologist and physician to the possibility of an inherited trait, with its implications for family screening. The tumours are usually benign and well demarcated but because of multicentricity and consequently increased risk of recurrence and/or progression to carcinoma, total thyroidectomy should be advocated. Copyright

Germline RET V804M mutation associated with multiple endocrine neoplasia type 2A

Most patients with genetic medullary thyroid carcinoma (MTC), including familial MTC and multiple endocrine neoplasia type 2 (MEN2), have a germline mutation in the RET proto-oncogene, located on chromosome 10q11.2. Germline mutations in the extracellular cysteinerich domain are found in 98 per cent, with 85 per cent having a mutation in codon 6341. Mutations in the intracellular domain are rare. Phaeochromocytoma and hyperparathyroidism (HPT) are classically associated with RET codon 634 mutation1. Malignancy and aggressiveness vary according to the specific codon mutation. Point mutation of the intracellular domain in exon 14, leading to a substitution of valine 804 by either leucine or methionine, has been described in familial MTC2,3. This report is of the first familial case of a V804M mutation associated with MEN2A.

Positional statement of the European Society of Endocrine Surgeons (ESES) on malignant adrenal tumors

Malignant adrenal tumors are very rare, and in addition, the criteria determining whether an adrenal neoplasm is benign or malignant are not precise. This explains that it is difficult to give clear recommendations, and in many cases, it is easier to recommend what should not be done than to recommend what should be done. The European Society of Endocrine Surgeons organized in Lyon (May 13–14, 2011) a workshop on malignant or potentially malignant adrenal tumors. In the year prior to the workshop, three working groups reviewed the available literature on pheochromocytomas (PCCs)/paragangliomas (PGLs), adrenocortical carcinomas, and metastases, respectively. In their respective field, these three working groups tried to grade the evidence for recommendations in accordance with accepted international standards. Results of their extensive update were presented during this workshop, and recommendations were discussed in three plenary sessions with input from all the participants. Articles were amended on the basis of the discussion at the workshop. Adrenocortical carcinomas