Clonal Composition of Human Adrenocortical Neoplasms

The mechanisms of tumorigenesis of adrenocortical neoplasms are still not understood. Tumor formation may be the result of spontaneous transformation of adrenocortical cells by somatic mutations. Another factor stimulating adrenocortical cell growth and potentially associated with formation of adrenal adenomas and, less frequently, carcinomas is the chronic elevation of proopiomelanocortin-derived peptides in diseases like ACTH-dependent Cushing's syndrome and congenital adrenal hyperplasia. To further investigate the pathogenesis of adrenocortical neoplasms, we studied the clonal composition of such tumors using X-chromosome inactivation analysis of the highly polymorphic region Xcen-Xp11.4 with the hybridization probe M27ß, which maps to a variable number of tandem repeats on the X-chromsome. In addition, polymerase chain reaction amplification of a phosphoglycerokinase gene polymorphism was performed. After DNA extraction from tumorous adrenal tissue and normal leukocytes in parallel, the active X-chromosome of each sample was digested with the methylation-sensitive restriction enzyme HpaII. A second digestion with an appropriate restriction enzyme revealed the polymorphism of the region Xcen-Xp11.4 and the phosphoglycerokinase locus. Whereas in normal polyclonal tissue both the paternal and maternal alleles are detected, a monoclonal tumor shows only one of the parental alleles. A total of 21 female patients with adrenal lesions were analyzed; 17 turned out to be heterozygous for at least one of the loci. Our results were as follows: diffuse (n = 4) and nodular (n = 1) adrenal hyperplasia in patients with ACTH-dependent Cushing's syndrome, polyclonal pattern; adrenocortical adenomas (n = 8), monoclonal (n = 7), as well as polyclonal (n = 1); adrenal carcinomas (n = 3), monoclonal pattern. One metastasis of an adrenocortical carcinoma showed a pattern most likely due to tumor-associated loss of methylation. In the special case of a patient with bilateral ACTH-independent macronodular hyperplasia, diffuse hyperplastic areas and a small nodule showed a polyclonal pattern, whereas a large nodule was monoclonal. We conclude that most adrenal adenomas and carcinomas are monoclonal, whereas diffuse and nodular adrenal hyperplasias are polyclonal. The clonal composition of ACTH-independent massive macronodular hyperplasia seems to be heterogeneous, consisting of polyclonal and monoclonal areas

P53 mutations in human adrenocortical neoplasms

The mechanisms of tumorigenesis of adrenocortical neoplasms have not been elucidated as yet. However, loss of heterozygosity at chromosomal locus 17p has been consistently observed in adrenocortical cancer. p53 is a recessive tumor suppressor gene located on chromosome 17p. Mutations in the p53 gene play an important role in the tumorigenesis of diverse types of human neoplasms including breast and colon cancers. More than 90% of all mutations discovered in such tumors have been detected in 4 hot spot areas that lie between exons 5 and 8. In contrast to wild-type p53, mutant p53 accumulates intracellularly and can be easily detected by immunohistochemistry. We therefore investigated the frequency of p53 mutations in human adrenocortical neoplasms using molecular biology and immunohistochemistry techniques. Five patients with adrenocortical adenomas (5 female; ages 39-72 yr), 11 patients with adrenocortical carcinomas (8 female, 3 male; ages 15- 50 yr), and two adrenocortical tumor cell lines were studied. After DNA extraction from frozen tumor tissue or paraffin-embedded material, exons 5 through 8 were amplified using the polymerase chain reaction and directly sequenced by the dideoxy termination method. Immunohistochemistry was performed on paraffin-embedded tumor specimens obtained during adrenalectomy using a monoclonal antibody reacting with both wild-type and mutant p53. Prevalence of mutations was adenomas, 0/5, carcinomas, 3/11, and adrenocortical cell lines, 2/2. Single point mutations were detected in 3 cases (exons 5, 6, and 7, respectively), and rearrangements of exon 7/8 and 8 were found in 2 cases. Immunohistochemistry detected strong nuclear and/or cytoplasmic p53 immunoreactivity in all adrenocortical carcinomas with point mutations of the p53 gene but not in adenomas and carcinomas with the wild-type sequence or with deletion/rearrangement of the p53 gene. We conclude that p53 plays a role in the tumorigenesis of adrenocortical carcinomas but is of less importance to benign adenomas

Physiopathological Implications of 7TM Receptors

Seven-transmembrane (7TM) receptors are one of the most important proteins involved in perception of extracellular stimuli and regulation of variety of intracellular signaling pathways. Divergence of receptor types, their ligands and signaling pathways makes 7TM receptors important factors in pathology of many diseases. This review focused on the main diseases in which involvement of 7TM receptors was established e.g., retinitis pigmentosa, severe obesity, and dwarfism. Recent findings of aberrant expression of 7TM receptors in development of cancer were also summarized

Follicular nodules (Thy3) of the thyroid: is total thyroidectomy the best option?

BACKGROUND: Identification of the best management strategy for nodules with Thy3 cytology presents particular problems for clinicians. This study investigates the ability of clinical, cytological and sonographic data to predict malignancy in indeterminate nodules with the scope of determining the need for total thyroidectomy in these patients. METHODS: The study population consisted of 249 cases presenting indeterminate nodules (Thy3): 198 females (79.5%) and 51 males (20.5%) with a mean age of 52.43 ± 13.68 years. All patients underwent total thyroidectomy. RESULTS: Malignancy was diagnosed in 87/249 patients (34.9%); thyroiditis co-existed in 119/249 cases (47.79%) and was associated with cancer in 40 cases (40/87; 45.98%). Of the sonographic characteristics, only echogenicity and the presence of irregular margins were identified as being statistically significant predictors of malignancy. 52/162 benign lesions (32.1%) and 54/87 malignant were hypoechoic (62.07%); irregular margins were present in 13/162 benign lesions (8.02%), and in 60/87 malignant lesions (68.97%). None of the clinical or cytological features, on the other hand, including age, gender, nodule size, the presence of microcalcifications or type 3 vascularization, were significantly associated with malignancy. CONCLUSIONS: The rate of malignancy in cytologically indeterminate lesions was high in the present study sample compared to other reported rates, and in a significant number of cases Hashimoto’s thyroiditis was also detected. Thus, considering the fact that clinical and cytological features were found to be inaccurate predictors of malignancy, it is our opinion that surgery should always be recommended. Moreover, total thyroidectomy is advisable, being the most suitable procedure in cases of multiple lesions, hyperplastic nodular goiter, or thyroiditis; the high incidence of malignancy and the unreliability of intraoperative frozen section examination also support this preference for total over hemi-thyroidectomy

A rare cause of recurrent spontaneous pneumothorax: Birt-hogg-dube syndrome

Birt-Hogg-Dube (BHD) syndrome is an unusual disorder characterized by the triad of cutaneous lesions, renal tumors and lung cysts. In cases with BHD syndrome, the frequency of recurrent pneumothorax is increased due to presence of multiple lung cysts. It is important to evaluate the BHD syndrome in differential diagnosis of recurrent pneumothorax especially with multiple lung cysts predominating in the lung base. In these patients, the presence of accompanying kidney and other tumors should be investigated. Herein, we report a case of BHD syndrome presenting with recurrent pneumothorax. © 2018 by Turkish Thoracic Society

Recent Advances and the Potential for Clinical Use of Autofluorescence Detection of Extra-Ophthalmic Tissues

The autofluorescence (AF) characteristics of endogenous fluorophores allow the label-free assessment and visualization of cells and tissues of the human body. While AF imaging (AFI) is well-established in ophthalmology, its clinical applications are steadily expanding to other disciplines. This review summarizes clinical advances of AF techniques published during the past decade. A systematic search of the MEDLINE database and Cochrane Library databases was performed to identify clinical AF studies in extra-ophthalmic tissues. In total, 1097 articles were identified, of which 113 from internal medicine, surgery, oral medicine, and dermatology were reviewed. While comparable technological standards exist in diabetology and cardiology, in all other disciplines, comparability between studies is limited due to the number of differing AF techniques and non-standardized imaging and data analysis. Clear evidence was found for skin AF as a surrogate for blood glucose homeostasis or cardiovascular risk grading. In thyroid surgery, foremost, less experienced surgeons may benefit from the AF-guided intraoperative separation of parathyroid from thyroid tissue. There is a growing interest in AF techniques in clinical disciplines, and promising advances have been made during the past decade. However, further research and development are mandatory to overcome the existing limitations and to maximize the clinical benefits

Neuroendocrine Tumors (NETs) : A population-based study of incidence and survival in Girona province, 1994-2004

Els tumors neuroendocrins (TNEs) són un grup de neoplàsies poc freqüents i heterogènies i amb un ampli espectre d'agressivitat. Hi ha molt poca informació epidemiològica a nivell mundial, l'objectiu d'aquest estudi ha estat el de reportar-ne les dades a la província de Girona. Hem inclòs tots els codis de la ICD-O3 que codifiquen un TNE, període 1994-2002. Hem identificat 698 tumors. Es reporten les dades tant de la casuística com les taxes d'incidència i supervivència de cada TNE per separat. Els resultats són consistents amb les publicacions europees. El fet d'haver reportat la incidència i la supervivència dels TNEs a Girona contribueix a un millor coneixement d'aquestes neoplàsies.Neuroendocrine tumors (NETs) belong to a rare and heterogeneous group of neoplasms with a wide range of aggressiveness. Little information is available about epidemiology of NETs in the World population. The objective of this study was to report the incidence and survival of these tumors in Girona province. We included all ICD-O3 codes that codified a NET, period 1994-2004. We identified 698 NETs. We reported our data and the calculated incidence and survival of each NET. Our results were consistent with other European reports. By providing the incidence and survival of NETs in Girona province, this study contributes to a better understanding of these rare tumors

Chromogranin A: From Laboratory to Clinical Aspects of Patients with Neuroendocrine Tumors

Background. Neuroendocrine tumors (NETs) are characterized by having behavior and prognosis that depend upon tumor histology, primary site, staging, and proliferative index. The symptoms associated with carcinoid syndrome and vasoactive intestinal peptide tumors are treated with octreotide acetate. The PROMID trial assesses the effect of octreotide LAR on the tumor growth in patients with well-differentiated metastatic midgut NETs. The CLARINET trial evaluates the effects of lanreotide in patients with nonfunctional, well-, or moderately differentiated metastatic enteropancreatic NETs. Everolimus has been approved for the treatment of advanced pancreatic NETs (pNETs) based on positive PFS effects, obtained in the treated group. Sunitinib is approved for the treatment of patients with progressive gastrointestinal stromal tumor or intolerance to imatinib, because a randomized study demonstrated that it improves PFS and overall survival in patients with advanced well-differentiated pNETs. In a phase II trial, pasireotide shows efficacy and tolerability in the treatment of patients with advanced NETs, whose symptoms of carcinoid syndrome were resistant to octreotide LAR. An open-label, phase II trial assesses the clinical activity of long-acting repeatable pasireotide in treatment-naive patients with metastatic grade 1 or 2 NETs. Even if the growth of the neoplasm was significantly inhibited, it is still unclear whether its antiproliferative action is greater than that of octreotide and lanreotide. Because new therapeutic options are needed to counter the natural behavior of neuroendocrine tumors, it would also be useful to have a biochemical marker that can be addressed better in the management of these patients. Chromogranin A is currently the most useful biomarker to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy

Intraoperative neuromonitoring versus visual nerve identification for prevention of recurrent laryngeal nerve injury in adults undergoing thyroid surgery

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effects of intraoperative neuromonitoring (IONM) versus visual nerve identification for prevention of recurrent laryngeal nerve injury in adults undergoing thyroid surgery