Preoperative Ultrasonography in the Evaluation of Suspected Familial Non-Medullary Thyroid Cancer: Are We Able to Predict Multifocality and Extrathyroidal Extension?

Family history of thyroid cancer increases the risk of harboring thyroid malignancies that end up having extrathyroidal extension (ETE) and multifocality on histology; some authors suggest a more aggressive surgical approach. Their pre-operative identification could allow more conservative surgical procedures if none of these features are suspected. Our aim was to assess if neck ultrasonography could identify or exclude multifocality or ETE in these patients to tailor the extent of surgery. This retrospective study included patients with previous thyroid surgery, ≥1 first-grade relative with thyroid cancer, and who had undergone pre-surgical ultrasound. ETE was suspected in the case of thyroid border interruption or gross invasion of perithyroidal tissues. Multiple suspicious nodules were defined as suspicion of multifocal cancer. The cohort consisted of 45 patients (median age 49 years, 40 with thyroid cancer, 30 females). The positive predictive value of ultrasonography in predicting multifocality and ETE was 57.14% (25.25-84.03) and 41.67% (21.5-65.1%), respectively, while the negative predictive values were 63.2% (56.4-69.4%) and 72.7% (63.3-80.5%). Pre-operative ultrasound examination is unable to reliably identify or exclude multifocal disease or extrathyroidal extension. In patients scheduled for surgery and with a first-degree relative affected by DTC, a "negative" pre-operative US report does not exclude the potential finding of multifocality and ETE at final histopathology.

Paraneoplastic Neuromyelitis Optica Spectrum Disorder Associated With Lung Adenocarcinoma: A Case Report.

Neuromyelitis Optica spectrum disorder is an inflammatory demyelinating disease affecting the central nervous system (CNS), characterized by triad optic neuritis, transverse myelitis, and area postrema syndrome. Antibodies directed against aquaporin-4 (AQP-4), a water channel expressed on the astrocytic membrane, are supposed to play a pathogenic role and are detected in ~80% of cases. Clinical signs of Neuromyelitis Optica spectrum disorder (NMOSD) in elderly patients should arouse the suspicion of paraneoplastic etiology. In this article, we discussed a case of a 76-year-old woman with a 2-month history of confusion, dysarthria, and progressive bilateral leg weakness. A whole-body CT scan showed a neoformation of 5 cm in diameter in the median lobe infiltrating the mediastinal pleura. The tumor had already spread to both the upper and lower right lobes, parietal pleura, and multiple lymph nodes. Pleural cytology revealed adenocarcinoma cells. The brain MRI documented hyperintense alteration in fluid-attenuated inversion recovery (FLAIR) images, involving the anterior portion of the corpus callosum and the periependymal white matter surrounding the lateral ventricles, with mild contrast enhancement on the same areas and meningeal tissue. T2-weighted spinal cord MRI sequences showed extended signal hyperintensity from bulbo-cervical junction to D7 metamer, mainly interesting the central component and the gray matter. Cerebrospinal fluid analysis revealed no neoplastic cells. Serum AQP-4 immunoglobulin (IgG) antibodies were found. Meanwhile, the patient rapidly developed progressive paraparesis and decreased level of consciousness. High-dose intravenous methylprednisolone therapy was started but her conditions rapidly deteriorated. No other treatment was possible.

Sonographic Risk Stratification Systems for Thyroid Nodules as Rule-Out Tests in Older Adults.

Ultrasonographic risk-stratification systems (RSS), including various Thyroid Imaging Reporting and Data Systems (TIRADS), were proposed to improve reporting and reduce the number of fine-needle aspiration biopsies. However, age might be a confounder since some suspicious ultrasonographic features lack specificity in elderly patients. We aimed to investigate whether the diagnostic performance of the RSS varied between age groups. All patients consecutively referred for thyroid biopsy between November 1, 2015, and March 10, 2020, were included. The malignancy risk of each nodule was estimated according to five RSS: the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi guidelines, the American College of Radiology (ACR) TIRADS, the American Thyroid Association guidelines, the European TIRADS, and the Korean TIRADS. Overall, 818 nodules (57 malignant) were evaluated. The malignancy rate was higher in patients ≤ 65 years (8.1%) than in patients > 65 years (3.8%; p = 0.02). All RSS confirmed a significant discriminative performance in both age groups, with a negative predictive value of 100% in patients > 65 years, although specificity was lower in older patients. The ACR TIRADS was the best performing in both age groups. RSS could avoid a sizable number of biopsies when applied as rule-out tests in elderly patients.

Expression of Leptin Receptor and Effects of Leptin on Papillary Thyroid Carcinoma Cells.

BACKGROUND: Obesity has been hypothesized to contribute to the aggressiveness of thyroid cancer through the production of abnormal levels of serum adipokines. Leptin receptor (OB-R) expression has also been documented in papillary thyroid cancer (PTC). AIM: In this translational study, we analyzed in vitro the effects of leptin on the growth and migration of thyroid cancer cells (TPC-1 and K1), the molecular mechanisms underlying leptin's action, and the influence of prolonged leptin exposure on cell response to a protein kinase inhibitor lenvatinib. The expression levels of OB-R mRNA and protein were also investigated in vivo in a series of aggressive PTCs divided into two groups based on the presence of the BRAF mutation. RESULTS: In TPC-1 and K1 cells, prolonged treatment with leptin (500 ng/ml for 96 h) resulted in a mild increase in the proliferation (about 20% over control only in K1 cells, p < 0.05) and in the migration of both cancer cell lines. Immunoblot analysis revealed a slight increase in the phosphorylation of AKT, but no effect on ß-catenin and phospho-ERK expressions. The inhibitory effects of lenvatinib on the viability of both cell lines were not influenced by the leptin treatment. OB-R transcript (in fresh tissues) and proteins (in formalin-fixed and paraffin-embedded specimens) were expressed in all PTC tissues examined, with no significant differences between BRAF-mutated and BRAF-wild-type tumors. CONCLUSIONS: These results demonstrate leptin's role in mildly increasing the aggressive phenotype of PTC cells but without influencing the action of lenvatinib. Further studies will clarify whether it is possible to target OB-R, expressed in all aggressive PTCs, as an adjuvant treatment approach for these malignancies.

Interobserver agreement of various thyroid imaging reporting and data systems.

Ultrasonography is the best available tool for the initial work-up of thyroid nodules. Substantial interobserver variability has been documented in the recognition and reporting of some of the lesion characteristics. A number of classification systems have been developed to estimate the likelihood of malignancy: several of them have been endorsed by scientific societies, but their reproducibility is yet to be assessed. We evaluated the interobserver variability of the AACE/ACE/AME, ACR, ATA, EU-TIRADS and K-TIRADS classification systems and the interobserver concordance in the indication to FNA biopsy. Two raters independently evaluated 1055 ultrasound images of thyroid nodules identified in 265 patients at multiple time points, in two separate sets (501 and 554 images). After the first set of nodules, a joint reading was performed to reach a consensus in the feature definitions. The interobserver agreement (Krippendorff alpha) in the first set of nodules was 0.47, 0.49, 0.49, 0.61 and 0.53, for AACE/ACE/AME, ACR, ATA, EU-TIRADS and K-TIRADS systems, respectively. The agreement for the indication to biopsy was substantial to near-perfect, being 0.73, 0.61, 0.75, 0.68 and 0.82, respectively (Cohen's kappa). For all systems, agreement on the nodules of the second set increased. Despite the wide variability in the description of single ultrasonographic features, the classification systems may improve the interobserver agreement that further ameliorates after a specific training. When selecting nodules to be submitted to FNA biopsy, that is main purpose of these classifications, the interobserver agreement is substantial to almost perfect.

Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism Due to Adrenal Incidentaloma: Results from a Single Center.

INTRODUCTION: This study was designed to evaluate the results of unilateral laparoscopic adrenalectomy in patients with subclinical hypercortisolism (SH) due to adrenal incidentaloma (AI) concerning the main cardiometabolic disorders. METHODS: We have studied between January 2000 to December 2015, 645 patients with AI (283 males and 362 females; mean age 61.9 ± 10 years) and we found 70 patients with SH (27 males and 43 females; mean age 61.9 ± 8.4 years). Twenty-six (37%) SH patients (6 males and 20 females; mean age 58.7 ± 7.1 years) underwent unilateral laparoscopic adrenalectomy, whereas 44 SH patients (21 males and 23 females; mean age 63.9 ± 9.9 years) performed a conservative treatment. All SH patients were evaluated at diagnosis and after follow-up (mean 12 months; range 9-15 months). RESULTS: In only SH patients undergoing unilateral adrenalectomy we found a statistical significant reduction of the arterial hypertension and metabolic syndrome (p < 0.05, respectively). In particular we observed a reduction of 24-h systolic blood pressure and "non-dipper" pattern (p < 0.05, respectively) evaluated with ambulatory blood pressure monitoring (ABPM). CONCLUSIONS: Our study confirm the high prevalence of SH in AI, and the unilateral laparoscopic adrenalectomy seemed to have a beneficial effect on some cardiometabolic disorders.

Plasma endothelin-1 levels in patients with resistant hypertension: effects of renal sympathetic denervation.

INTRODUCTION: Resistant arterial hypertension (RHT) is defined as poor controlled blood pressure (BP) despite optimal doses of three or more antihypertensive agents, including a diuretic. In the development of RHT, hyperactivity of sympathetic (SNS) and renin-angiotensin-aldosterone (SRAA) systems are involved, and SNS is a potent stimulator of vasoactive endothelin-1 (ET-1) peptide. Renal sympathetic denervation (RSD) through disrupting renal afferent and efferent nerves attenuates SNS activity. MATERIAL AND METHODS: We carried out pilot study investigating the effect of RSD on BP and plasma ET-1 levels in consecutive 9 RHT patients (7 male and 2 female, mean age of 56 ± 13.3). RESULTS: After 12 months of the RSD, we observed a significant reduction of BP office, 24-h ambulatory BP monitoring (ABPM) (p < 0.05, respectively), and "non-dipping" pattern (from 55% to 35%) (p < 0.05). Moreover, RSD significantly decreased plasma ET-1 levels in both renal artery (at right from 21.8 ± 4.1 to 16.8 ± 2.9 pg/ml; p = 0.004; at left from 22.1 ± 3.7 to 18.9 ± 3.3 pg/ml; p = 0.02). We observed positive correlations between plasma renal arteries ET-1 levels and systolic BP values at ABPM [Global-SBP (r = 0.58; p < 0.01), Diurnal-SBP (r = 0.51; p < 0.03) and Nocturnal-SBP (r = 0.58; p < 0.01), respectively]. DISCUSSION: Our data confirmed the positive effects of RSD on BP values in patients with RHT, and showed a possible physio-pathological role of ET-1. KEY MESSAGES RSD is associated to a significant reduction of plasma ET-1 levels, representing an useful tool into reduction of BP in RHT patients.

A case report of subclinical hypercortisolism due to adrenal incidentaloma complicated by myasthenia gravis after adrenalectomy.

A 62-year-old woman was admitted for evaluation of an incidentally discovered adrenal mass and hypertension. CT scan revealed a 7 cm mass in the right adrenal gland. After careful examination, the patient was diagnosed with subclinical hypercortisolism (SH). Adrenalectomy was performed. Histopathological examination showed an adrenocortical adenoma. Symptoms and signs of myasthenia gravis appeared 5 months later. CT of the chest showed a solid tissue mass in the mediastinum. The patient underwent a sternotomy with excision of the tumor, which histologically proved to be a type 2B thymoma. We describe a rare case of SH due to an incidentally discovered adrenocortical adenoma in a patient who manifested myasthenia gravis after surgical remission of the cortisol excess.

Adrenal Pheochromocytoma Incidentally Discovered in a Patient With Parkinsonism.

To evaluate the diagnostic route of pheochromocytoma (PHEO) in a patient under dopaminergic treatment.A 70-year-old man with Parkinsonism and under treatment with levodopa and carbidopa came to our observation for evaluation of arterial hypertension and right adrenal mass discovered incidentally.To evaluate adrenal hormone levels we performed a dexamethasone suppression test, plasma aldosterone levels and 24-hr urinary metanephrine, which revealed elevated levels of catecholamines metabolities. 123-I-metaiodobenzylguanidine SPECT scintiscan revealed raised activity within the right adrenal gland concordant with the mass. The diagnosis of PHEO was posed and an elective laparoscopic adrenalectomy was performed; histopathological examination confirmed the PHEO diagnosis.Recently the coexistence of PHEO and Parkinsonism is a very rare association of diseases, with only 3 cases reported in literature. In this article, another case is reported and diagnostic procedures are discussed.

A NOVEL DOUBLE MUTATION VAL648ILE AND VAL804LEU OF RET PROTO-ONCOGENE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE 2.

OBJECTIVE: We report the case of a female patient with multiple endocrine neoplasia type 2A (MEN2A) who was found to have a double mutation in the RET (rearranged during transfection) proto-oncogene. METHODS: RET mutational analysis was performed by Sanger DNA sequencing. RESULTS: The proband was a compound heterozygote for the RET germline mutations Val648Ile and Val804Leu on exons 11 and 14, respectively. Genetic analysis of family members showed the presence of the Val648Ile mutation in all except 1 daughter who carried the Val804Leu mutation. However, none of them showed any clinical, biochemical, or histologic signs of neoplastic disease either in the thyroid or adrenal gland. Furthermore, a daughter and the proband's sister who underwent a prophylactic thyroidectomy did not show pathologic evidence of C-cell disease. CONCLUSIONS: We hypothesize that the combined effect of the 2 mutations may have induced the development of pheochromocytoma (PHEO) in our patient. Thus, in the presence of single RET-induced mild medullary thyroid cancer (MTC) phenotype, the search for additional genetic anomalies may lead to the discovery of rare but potentially more aggressive double mutation genotypes.

Multiple catecholamine-secreting paragangliomas: diagnosis after hemorrhagic stroke in a young woman.

OBJECTIVE: To describe a case of multiple catecholamine-secreting paragangliomas, with a hemorrhagic stroke as the main clinical manifestation. METHODS: We present a case report with clinical, laboratory, histologic, and genetic details. RESULTS: A 23-year-old woman with a history of hypertension treated with orally administered medications presented to our emergency department because of sudden onset of hemiplegia of the left side of the body. A computed tomographic scan of the brain showed a right frontoparietal hematoma, and her blood pressure was 185/115 mm Hg. She was admitted to the Department of Neurosurgery, and an external drain was inserted to evacuate the hematoma. She was then referred to the Department of Clinical Sciences, where a search for possible secondary causes of hypertension was undertaken. Substantially elevated urinary levels of vanillylmandelic acid and metanephrines were found, and a pheochromocytoma was suspected. Abdominal computed tomographic scans revealed a large retroperitoneal mass (3.6 by 4 cm) and similar smaller lesions in the right adrenal gland, between the aorta and the vena cava, and in the left paraaortic area. Iodine I 123 metaiodobenzylguanidine scintigraphy showed high uptake in those same areas, consistent with the diagnosis of multiple catecholamine-secreting paragangliomas. After adequate control of the patient's hypertension was achieved with an alpha1-adrenergic receptor blocker, a Ca2+ antagonist, and a beta-adrenergic blocking agent, the tumors were excised in the Department of Surgery. The histopathologic findings confirmed the diagnosis of multiple paragangliomas. The genetic analysis demonstrated an exon 4 mutation in codon 109 (CAA>TAA, Gln>Stop) of the SDHD gene. CONCLUSION: Although cerebral hemorrhage is an unusual complication of pheochromocytomas or paragangliomas, early recognition of the characteristic symptoms of headache, palpitations, and diaphoresis in a patient with hypertension and prompt appropriate intervention can minimize the morbidity associated with such tumors and prevent a potentially fatal outcome.

Vasoactive intestinal peptide (VIP): a new neuroendocrine marker of clinical progression in chronic heart failure?

OBJECTIVE: Vasoactive intestinal peptide (VIP) is a powerful vasodilatory neuropeptide with positive inotropic and chronotropic properties. The aim of the study was to investigate the pathophysiological role of VIP in heart failure. DESIGN AND RESULTS: VIP was assayed in plasma within the first in-hospital day in 52 patients with heart failure due to dilated cardiomyopathy. The concentration of VIP was: (i) higher in patients than in healthy subjects; (ii) higher in elderly but not in younger patients compared with healthy controls; (iii) inversely related to NYHA class: higher in NYHA 2 than in NYHA > 2 patients and in normal subjects, in both young and elderly groups; (iv) not correlated with echocardiographic parameters and (v) not influenced by the aetiology of dilated cardiomyopathy. CONCLUSIONS: The physiological properties of VIP suggest that the increased plasma concentrations in patients with heart failure contribute to restore the compromised haemodynamic balance either by improving myocardial performance or by counteracting the harmful effects related to simultaneous activation of other neuroendocrine systems, i.e. the sympathetic and renin-angiotensin systems. Decreased VIP concentrations are related to progressive worsening of heart failure. The higher VIP concentrations in elderly patients compared with healthy controls suggest that the capacity to increase VIP production is preserved in older people.