Central diabetes insipidus and pituitary stalk thickening in adults: distinction of neoplastic from non-neoplastic lesions.

CONTEXT: Association of central diabetes insipidus (CDI) and pituitary stalk thickening (PST) may have several etiologies (including malignancies) and differential diagnosis remains often difficult. OBJECTIVE: The purpose of this study was to identify which clinical, biochemical or radiological features could help clinicians to make an etiological diagnosis, especially distinguishing neoplastic from non-neoplastic pituitary stalk lesions. DESIGNS AND METHODS: We retrospectively analyzed clinical, biochemical, radiological and histological data of 38 adult patients diagnosed with CDI and PST of proven etiology. RESULTS: Of the 38 pituitary stalk lesions included, 11 (29%) were neoplastic. A histopathological diagnosis was obtained in 22/38 (58%) patients. The three most frequently observed etiologies of PST were neuroinfundibulitis (34%), germinoma (21%) and histiocytosis (18%). Pituitary stalk thickness was larger for neoplastic lesions, particularly germinomas. Male gender and a very young age were statistically associated with a risk of germinoma. At least one anterior pituitary deficit was observed in nearly 60% of patients. Patients with neoplastic PST were more affected by multiple anterior pituitary dysfunction than patients with benign PST. A high serum prolactin level was individually the best predictor of a neoplastic origin (90% sensitivity and 60% specificity for a serum prolactin level 1.27-fold above the normal upper limit (ULN)). CONCLUSION: We confirm a relatively high risk of malignancy in adult patients presenting with the association of CDI and PST. Young age, male gender, a very large thickening of the stalk, multiple anterior pituitary deficits and prolactin above 1.3× ULN increase the likelihood of a neoplastic origin.

Thyroid lobectomy is an effective option for unilateral benign nodular disease.

OBJECTIVE: The use of thyroid lobectomy in the treatment of unilateral, benign nodules is limited by the potential of nodular recurrence in the remaining lobe. This study aimed to assess the rate and clinical impact of nodular recurrence in the contralateral lobe after thyroid lobectomy and to identify predictive factors of recurrence. DESIGN: Single-centre retrospective study. PATIENTS: Records of patients that underwent lobectomy for unilateral thyroid nodules between 1991 and 2010 were reviewed and 270 patients were included. Exclusion criteria were: presence of contralateral nodule(s) ≥5 mm on preoperative ultrasound, diagnosis of cancer necessitating completion thyroidectomy or pseudonodules. Recurrence was defined as the occurrence of nodule(s) ≥5 mm in the remaining lobe on at least one postoperative ultrasound. A set of clinical, imaging, histological and biochemical parameters was tested as predictors of recurrence using logistic regression. RESULTS: After a median follow-up of 78 months (range, 12-277 months), the global recurrence rate was 42% and recurrence of nodules of a size ≥1 cm occurred in 19%. Reoperation rate was 1·1%. 90% of patients were treated postoperatively by levothyroxine. Median time to nodular recurrence was 4 years. Preoperative contralateral lobe volume and resected thyroid weight were identified as significant predictors of recurrence (P = 0·045 and P = 0·03 respectively). CONCLUSIONS: Thyroid lobectomy is an effective therapeutic strategy for unilateral, benign nodules, resulting in a low rate of clinically relevant nodular relapse in a mildly iodine-deficient area. Patients with uninodular disease and a contralateral lobe of normal size are particularly good candidates for lobectomy.

Iodotyrosine deiodinase defect identified via genome-wide approach.

CONTEXT: Diagnosis of congenital hypothyroidism is hampered by the heterogeneity of inborn errors of thyroid metabolism and the possible delay in hypothyroidism development leading to missed cases by neonatal screen. OBJECTIVE: In the current study, we used a whole-genome approach to identify the mutation responsible for severe hypothyroidism and a huge goiter in the eldest child born to healthy first cousins. RESULTS: We identified a homozygous mutation of the iodotyrosine deiodinase gene (IYD). We delineated the phenotype of this defect in detail, including urinary monoiodotyrosine (MIT) and diiodotyrosine (DIT) excretion. Moreover, a 4.5-yr-old sister was found homozygous for the mutation. Her clinical and biological data were normal, except for elevated MIT and DIT excretion. The urinary loss of MIT and DIT iodine observed in most affected individuals was quite limited compared to the total iodine loss, except for the hypothyroid homozygote. Hypothyroidism could therefore be partially induced by a relative iodine deficiency caused by urinary iodine loss through MIT and DIT excretion, even in cases of normal iodine intake. The wide inter- and intrafamilial variability of the disease severity remains unclear. CONCLUSIONS: Besides refining the phenotype of the IYD defect, our observation shows that a global, genome-wide approach to the heterogeneous inborn thyroid defects was efficient in rapidly identifying the mutation in the proband and the disease recurrence in the still euthyroid sister. Although facilitated by consanguinity in this family, novel sequencing techniques will soon make whole-genome approaches readily amenable to more common cases.

Hydrogen peroxide induces DNA single- and double-strand breaks in thyroid cells and is therefore a potential mutagen for this organ.

DNA double-strand breaks (DSBs) are considered as one of the primary causes of cancer but their induction by hydrogen peroxide (H(2)O(2)) is still controversial. In this work, we studied whether the high levels of H(2)O(2) produced in the thyroid to oxidize iodide could induce DNA modifications. Scores of DNA damage, in terms of strand breaks, were obtained by comet assay (alkaline condition for single-strand breaks (SSBs) and neutral condition for DSBs). We demonstrated that in a rat thyroid cell line (PCCl3), non-lethal concentrations of H(2)O(2) (0.1-0.5 mmol/l) as well as irradiation (1-10 Gy) provoked a large number of SSBs ( approximately 2-3 times control DNA damage values) but also high levels of DSBs (1.2-2.3 times control DNA damage values). We confirmed the generation of DSBs in this cell line and also in human thyroid in primary culture and in pig thyroid slices by measuring phosphorylation of histone H2AX. L-Buthionine-sulfoximine, an agent that depletes cells of glutathione, decreased the threshold to observe H(2)O(2)-induced DNA damage. Moreover, we showed that DNA breaks induced by H(2)O(2) were more slowly repaired than those induced by irradiation. In conclusion, H(2)O(2) causes SSBs and DSBs in thyroid cells. DSBs are produced in amounts comparable with those observed after irradiation but with a slower repair. These data support the hypothesis that the generation of H(2)O(2) in thyroid could also play a role in mutagenesis particularly in the case of antioxidant defense deficiency.

Gene expression in RET/PTC3 and E7 transgenic mouse thyroids: RET/PTC3 but not E7 tumors are partial and transient models of human papillary thyroid cancers.

We studied gene expression profiles in two mouse models of human thyroid carcinoma: the Tg-RET/PTC3 (RP3) and Tg-E7 mice. RP3 fusion gene is the most frequent mutation found in the first wave post-Chernobyl papillary thyroid cancers (PTCs). E7 is an oncoprotein derived from the human papillomavirus 16 responsible for most cervical carcinoma in women. Both transgenic mice develop thyroid hyperplasia followed by solid differentiated carcinoma in older animals. To understand the different steps leading to carcinoma, we analyzed thyroid gene expression in both strains at different ages by microarray technology. Important biological processes were differentially regulated in the two tumor types. In E7 thyroids, cell cycle was the most up-regulated process, an observation consistent with the huge size of these tumors. In RP3 thyroids, contrary to E7 tumors, several human PTC characteristics were observed: overexpression of many immune-related genes, regulation of human PTC markers, up-regulation of EGF-like growth factors and significant regulation of angiogenesis and extracellular matrix remodeling-related genes. However, similarities were incomplete; they did not concern the overall gene expression and were not conserved in old animals. Therefore, RP3 tumors are partial and transient models of human PTC. They constitute a good model, especially in young animals, to study the respective role of the biological processes shared with human PTC and will allow testing drugs targeting these validated variables.

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology.

The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18,000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.