RESUMEN
PURPOSE: Adrenocortical carcinoma (ACC), a rare malignancy of the adrenocortex, is characterized by a crosstalk between the adipose microenvironment and tumor. Here, we assessed the involvement of carbonic anhydrase (CA) enzymes III and IX (CAIII and CAIX), in the metabolic alterations of the adipose tissue characterizing obesity and in the local crosstalk between the tumor adipose microenvironment and ACC. RESULTS/METHODS: CAIII and CAIX expression is altered in visceral adipose tissue (VAT) in obesity and in ACC. A significant CAIX upregulation was present in ACC at advanced stages (n = 14) (fold increase FI = 7.4 ± 0.1, P < 0.05) associated with lower CAIII levels (FI = 0.25 ± 0.06, P < 0.001), compared with lower stages (n = 9). In vitro coculture between visceral adipose stem cells (ASCs) and ACC cell lines, H295R and MUC-1, mimicking the interaction occurring between VAT and advanced ACC, showed a significant CAIX upregulation in H295R but not in MUC-1 cells, and a decreased expression of CAIII. The effect on adipose cells was different when cocultured with H295R or MUC-1 cells. Coculture did not modulate CAIII expression in ASCs, which, however, was significantly downregulated with H295R (FI = 0.34 ± 0.11, P < 0.05) and upregulated by MUC-1 when cocultured ASCs were induced to differentiate toward adipocytes, with an expression profile similar to what found in VAT of obese subjects. CAIX expression was markedly increased in ASCs cocultured with H295R and to a less extent following adipogenesis induction (FI = 150.9 ± 46.5 and FI = 4.6 ± 1.1, P < 0.01, respectively). CONCLUSION: Our findings highlight a modulation of CAIII and CAIX in the metabolic crosstalk between ACC and its local adipose microenvironment, suggesting that CAs might represent a potential target for novel anticancer therapies.
Asunto(s)
Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Anhidrasa Carbónica III , Anhidrasas Carbónicas , Humanos , Anhidrasa Carbónica IX , Antígenos de Neoplasias/metabolismo , Anhidrasas Carbónicas/metabolismo , Obesidad , Microambiente TumoralRESUMEN
BACKGROUND: Pheochromocytoma (PHEO) and paraganglioma (PGL) are rare neuroendocrine tumors releasing catecholamines. Metastatic pheochromocytomas/paragangliomas (PPGLs) occur in about 5-26% of cases. To date, the management of patients affected by metastatic disease is a challenge in the absence of guidelines. AIM: The aim of this study was to evaluate the overall survival (OS) and the progression-free survival (PFS) in metastatic PPGLs. METHODS: Clinical data of 20 patients referred to the Careggi University Hospital (Florence, Italy) were retrospectively collected. Follow-up ranged from 1989 to 2019. Site and size of primary tumor, biochemical activity, genetic analysis and employed therapies were considered. Data were analyzed with SPSS version 27. RESULTS: Nine PHEOs (45%) and 11 PGLs (55%) were enrolled. Median age at diagnosis was 43.5 years [30-55]. Mean follow-up was 104.6 ± 89.3 months. Catecholamines were released in 70% of cases. An inherited disease was reported in 50% of patients. OS from the initial diagnosis (OSpt) and from the metastatic appearance (OSmtx) were lower in older patients (OSpt p = 0.028; OSmtx p < 0.001), abdominal PGLs (OSpt p = 0.007; OSmtx p = 0.041), larger tumors (OSpt p = 0.008; OSmtx p = 0.025) and sporadic disease (OSpt p = 0.013; OSmtx p = 0.008). CONCLUSION: Our data showed that older age at the initial diagnosis, sympathetic extra-adrenal localization, larger tumors and wild-type neoplasms are related to worse prognosis. Notably, the employed therapies do not seem to influence the survival of our patients. At present, effective treatments for metastatic PPGLs are missing and a multidisciplinary approach is indispensably required.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/terapia , Paraganglioma/terapia , Feocromocitoma/terapia , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Neoplasias de las Glándulas Suprarrenales/mortalidad , Neoplasias de las Glándulas Suprarrenales/patología , Adulto , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Paraganglioma/diagnóstico , Paraganglioma/mortalidad , Paraganglioma/patología , Feocromocitoma/diagnóstico , Feocromocitoma/mortalidad , Feocromocitoma/patología , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Espera Vigilante/estadística & datos numéricosRESUMEN
BACKGROUND: Metastatic pheochromocytomas and paragangliomas (PPGLs) occur in about 5-26% of cases and are characterized by a heterogeneous prognosis. Metastases can be synchronous at the initial diagnosis, but they can occur also many years after surgery for the primary tumor. To date, the treatment of patients affected by metastatic PPGLs represents a clinical challenge because of the lack of guidelines. AIM: The aim of this article is to review the available management options and their impact on the outcomes of patients with metastatic PPGLs. RESULTS: Generally, treatments are not curative. Surgery, when possible, can be used to reduce hormonal symptoms and cardiovascular morbidity. Chemotherapy plays a role in patients with high burden tumor and rapid disease progression. Tyrosine kinases inhibitors (TKIs) might be considered for their ability to block the angiogenesis and cell growth. Radiation therapy and interventional radiology techniques can help in the management of local metastases to control symptoms and avoid tumor progression. On the other hand, peptide receptor radionuclide therapy (PRRT), using 90Y or 177Lu-DOTATATE, could be a promising therapy. In addition, high specific 131I-MIBG was approved by the Food and Drug Administration (FDA) in the US for the treatment of patients affected by metastatic and unresectable 131I-MIBG positive PPGLs. Considering the different pathways involved in the pathogenesis of PPGLs, several target therapies have been proposed and are under evaluation in clinical trials. CONCLUSIONS: The choice of the appropriate treatment should be based on multidisciplinary and personalized approach taking into account the rarity and the variability of these tumors.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Paraganglioma/tratamiento farmacológico , Feocromocitoma/tratamiento farmacológico , Neoplasias de las Glándulas Suprarrenales/secundario , Animales , Manejo de la Enfermedad , Humanos , Paraganglioma/patología , Feocromocitoma/patología , PronósticoRESUMEN
PURPOSE: Nowadays, no human neuroendocrine cell models derived from the neural crest are available. In this study, we present non-transformed long-term primary Neural Crest Cells (NCCs) isolated from the trunk region of the neural crest at VIII-XII gestational weeks of human foetuses obtained from voluntary legal abortion. METHODS AND RESULTS: In NCC, quantitative real-time RT PCR demonstrated the expression of neural crest specifier genes, such as Snail1, Snail2/SLUG, Sox10, FoxD3, c-Myc, and p75NTR. Moreover, these cell populations expressed stemness markers (such as Nanog and nestin), as well as markers of motility and invasion (TAGLN, MMP9, CXCR4, and CXCR7), and of neuronal/glial differentiation (MAP2, GFAP, SYP, and TAU). Functional analysis demonstrated that these cells not only possessed high migration properties, but most importantly, they expressed markers of sympatho-adrenal lineage, such as ASCL1 and tyrosine hydroxylase (TH). Moreover, the expression of TH increased after the induction with two different protocols of differentiation towards neuronal and sympatho-adrenal phenotypes. Finally, exposure to conditioned culture media from NCC induced a mature phenotype in a neuronal cell model (namely SH-SY5Y), suggesting that NCC may also act like Schwann precursors. CONCLUSION: This unique human cell model provides a solid tool for future studies addressing the bases of human neural crest-derived neuroendocrine tumours.
Asunto(s)
Separación Celular , Feto/citología , Cresta Neural/citología , Células Neuroendocrinas/citología , Diferenciación Celular , Línea Celular , Movimiento Celular , Separación Celular/métodos , Femenino , Humanos , Cresta Neural/embriología , Cresta Neural/fisiología , Células Neuroendocrinas/fisiología , Fenotipo , Embarazo , Cultivo Primario de CélulasRESUMEN
BACKGROUND: The increasing frequency in the diagnosis of thyroid nodules has raised a growing interest in the search for new diagnostic tools to better select patients deserving surgery. In 2014, the major Italian Societies involved in the field drafted a new cytological classification, to better stratify pre-surgical risk of thyroid cancer, especially for the indeterminate category, split into TIR3A and TIR3B subclasses, associated to different therapeutic decisions. MATERIALS AND METHODS: This retrospective cross-sectional survey analyzed thyroid fine-needle aspiration biopsy performed at our outpatient clinic before and after the introduction of the new SIAPEC-IAP consensus in May 2014. RESULTS: 8956 thyroid nodules were included in the analysis: 5692 were evaluated according to the old classification and 3264 according to the new one. The new criteria caused the overall prevalence of TIR3 to increase from 6.1 to 20.1%. Of those, 10.7 and 9.4% were included in the TIR3A and TIR3B subgroups, respectively. Each of the 213 TIR3B nodules underwent surgery and 86 (40.4%) were diagnosed as thyroid cancer, while among the 349 TIR3A nodules, only 15 of the 60 that underwent surgery were found to be thyroid cancer. CONCLUSIONS: This analysis shows that the new SIAPEC-IAC criteria significantly increased the proportion of the overall TIR3 diagnosis. The division of TIR3 nodules into two subgroups (A and B) allowed a better evaluation of the oncologic risk and a better selection of patients to be referred to surgery.
Asunto(s)
Academias e Institutos/normas , Internacionalidad , Sociedades Médicas/normas , Nódulo Tiroideo/clasificación , Nódulo Tiroideo/diagnóstico por imagen , Estudios Transversales , Femenino , Humanos , Italia/epidemiología , Masculino , Estudios Retrospectivos , Neoplasias de la Tiroides/clasificación , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/epidemiología , Nódulo Tiroideo/epidemiologíaRESUMEN
Over the last decade, the development of novel and high penetrance genomic approaches to analyze biological samples has provided very new insights in the comprehension of the molecular biology and genetics of tumors. The use of these techniques, consisting of exome sequencing, transcriptome, miRNome, chromosome alteration, genome, and epigenome analysis, has also been successfully applied to adrenocortical carcinoma (ACC). In fact, the analysis of large cohorts of patients allowed the stratification of ACC with different patterns of molecular alterations, associated with different outcomes, thus providing a novel molecular classification of the malignancy to be associated with the classical pathological analysis. Improving our knowledge about ACC molecular features will result not only in a better diagnostic and prognostic accuracy, but also in the identification of more specific therapeutic targets for the development of more effective pharmacological anti-cancer approaches. In particular, the specific molecular alteration profiles identified in ACC may represent targetable events by the use of already developed or newly designed drugs enabling a better and more efficacious management of the ACC patient in the context of new frontiers of personalized precision medicine.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/diagnóstico , Genómica/métodos , Medicina de Precisión , Transcriptoma , Neoplasias de la Corteza Suprarrenal/genética , Carcinoma Corticosuprarrenal/genética , Humanos , PronósticoRESUMEN
BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Neoplasias Óseas/secundario , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/secundario , Recurrencia Local de Neoplasia/patología , Neoplasias de la Corteza Suprarrenal/mortalidad , Carcinoma Corticosuprarrenal/mortalidad , Neoplasias Óseas/mortalidad , Europa (Continente) , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Pulmonares/mortalidad , Metástasis Linfática , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: Rare endocrine-metabolic diseases (REMD) represent an important area in the field of medicine and pharmacology. The rare diseases of interest to endocrinologists involve all fields of endocrinology, including rare diseases of the pituitary, thyroid and adrenal glands, paraganglia, ovary and testis, disorders of bone and mineral metabolism, energy and lipid metabolism, water metabolism, and syndromes with possible involvement of multiple endocrine glands, and neuroendocrine tumors. Taking advantage of the constitution of a study group on REMD within the Italian Society of Endocrinology, consisting of basic and clinical scientists, a document on the taxonomy of REMD has been produced. METHODS AND RESULTS: This document has been designed to include mainly REMD manifesting or persisting into adulthood. The taxonomy of REMD of the adult comprises a total of 166 main disorders, 338 including all variants and subtypes, described into 11 tables. CONCLUSIONS: This report provides a complete taxonomy to classify REMD of the adult. In the future, the creation of registries of rare endocrine diseases to collect data on cohorts of patients and the development of common and standardized diagnostic and therapeutic pathways for each rare endocrine disease is advisable. This will help planning and performing intervention studies in larger groups of patients to prove the efficacy, effectiveness, and safety of a specific treatment.
Asunto(s)
Enfermedades del Sistema Endocrino/clasificación , Endocrinología/clasificación , Enfermedades Raras/clasificación , Informe de Investigación , Adulto , Clasificación , Enfermedades del Sistema Endocrino/diagnóstico , Endocrinología/métodos , Femenino , Humanos , Masculino , Enfermedades Raras/diagnósticoRESUMEN
Pheochromocytoma and paraganglioma are rare tumors of sympathetic or parasympathetic origin, presenting with a highly variable clinical picture. Rarity, as well as biological, clinical, and genetic heterogeneity are barriers to initiate prospective studies that help to establish clinical guidelines. The best management of these patients relies on the experience of a multidisciplinary team. The ultimate outcome can benefit from adequate pre-surgical evaluation and treatment as well as an accurate post-surgical follow-up. Long-term follow-up is mandatory in all patients, but is particularly important in specific familial cases such as those with an SDHB mutation where the risks of recurrence are higher. The surgical approach varies depending on tumor size, location, and surgeon's personal attitude and experience. In this paper, we summarize recommendations, based mostly on authors' and other experts' personal experiences, for the best possible management of patients prior, during and after surgery, as well as when pheochromocytoma is diagnosed during pregnancy.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/cirugía , Paraganglioma/cirugía , Feocromocitoma/cirugía , Complicaciones Neoplásicas del Embarazo/cirugía , Neoplasias de las Glándulas Suprarrenales/enfermería , Femenino , Humanos , Masculino , Paraganglioma/enfermería , Atención Perioperativa , Feocromocitoma/enfermería , Embarazo , Complicaciones Neoplásicas del Embarazo/enfermeríaRESUMEN
Adrenocortical carcinomas (ACCs) overexpress insulin-like growth factor 2 (IGF2), that drives a proliferative autocrine loop by binding to IGF1R and IR, but IGF1R/IR-targeted therapies failed in ACC patients. The cytoskeleton actin-binding protein filamin A (FLNA) impairs IR signalling in melanoma cells. Aims of this study were to test FLNA involvement in regulating IGF1R and IR responsiveness to both IGF2 and inhibitors in ACC. In ACC cells H295R and SW13 and primary cultures (1ACC, 4 adenomas) we found that IGF1R and IR interacted with FLNA, and FLNA silencing increased IGF1R and reduced IR expression, with a downstream effect of increased cell proliferation and ERK phosphorylation. In addition, FLNA knockdown potentiated antiproliferative effects of IGF1R/IR inhibitor Linsitinib and IGF1R inhibitor NVP-ADW742 in H295R. Finally, Western blot showed lower FLNA expression in ACCs (n = 10) than in ACAs (n = 10) and an inverse correlation of FLNA/IGF1R ratio with ERK phosphorylation in ACCs only. In conclusion, we demonstrated that low FLNA levels enhance both IGF2 proliferative effects and IGF1R/IR inhibitors efficacy in ACC cells, suggesting FLNA as a new factor influencing tumor clinical behavior and the response to the therapy with IGF1R/IR-targeted drugs.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Biomarcadores de Tumor/metabolismo , Filaminas/metabolismo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor de Insulina/antagonistas & inhibidores , Citoesqueleto de Actina/metabolismo , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/metabolismo , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/metabolismo , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Filaminas/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Imidazoles/farmacología , Factor II del Crecimiento Similar a la Insulina/genética , Mitógenos/farmacología , Pirazinas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Transducción de Señal , Células Tumorales CultivadasRESUMEN
Primary Aldosteronism (PA) is a disorder of the adrenal zona glomerulosa (ZG) in which aldosterone secretion is increased and is relatively autonomous of normal regulatory mechanisms. A recent conference in Munich organized by Prof. Reincke addressed advances and challenges related to the screening, diagnosis, and identification of uni- and bilateral involvement of the diseased adrenal of PA. Some infrequently addressed issues are described herein. We postulate that most cases of PA are due to the activation by unknown mechanisms of subset of cells resulting in the formation of a multiple foci or nodules of hyperactive zona glomerulosa cells. This implies that one or several yet unidentified stimuli can drive aldosterone overproduction, as well as the proliferation of aldosterone-producing cells. Current diagnostic procedures allow to determine whether inappropriate aldosterone production is driven by one or both adrenal glands and thus to establish optimal treatment.
Asunto(s)
Endocrinología/tendencias , Hiperaldosteronismo/terapia , Neoplasias de la Corteza Suprarrenal/complicaciones , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/metabolismo , Adenoma Corticosuprarrenal/complicaciones , Adenoma Corticosuprarrenal/diagnóstico , Adenoma Corticosuprarrenal/metabolismo , Aldosterona/sangre , Diagnóstico Diferencial , Endocrinología/métodos , Bocio Nodular/diagnóstico , Bocio Nodular/metabolismo , Humanos , Hiperaldosteronismo/sangre , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/etiología , Renina/sangreRESUMEN
Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224-6.343; OR 1.467 95% CI 1.202-1.792, respectively; Hosmer-Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930-0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866-0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285-2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.
Asunto(s)
Carcinoma Corticosuprarrenal/genética , Biomarcadores de Tumor/metabolismo , Metilación de ADN/genética , Factor II del Crecimiento Similar a la Insulina/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
In the last few years several papers have reported on the association between mutations of the genes encoding the structural (SDHC, SDHD) and catalytic (SDHB) subunits of succinate dehydrogenase and the occurrence of hereditary pheochromocytomas/paragangliomas (Pheo/PGL) syndromes. We diagnosed a malignant extraadrenal Pheo in a 38-yr-old man with abdominal lesions; many areas of increased uptake at octreoscan scintigraphy in the skeleton indicated metastatic disease. We then approached genetic analysis through the screening of the SDHB, SDHC, and SDHD genes. Here we report a heterozygous G>A transversion at position +1 of intron 4 of SDHB gene. To clarify this mutation we performed cDNA analysis by RT-PCR and we assume that the splice site mutation in intron 4 abolishes the consensus splice donor sequence leading to an in-frame deletion of 18 amino acid. This finding indicates once again that SDHB mutations could predispose to malignant Pheo.
Asunto(s)
Neoplasias Abdominales/genética , Feocromocitoma/genética , Succinato Deshidrogenasa/genética , 3-Yodobencilguanidina , Adulto , Secuencia de Bases , Resultado Fatal , Femenino , Eliminación de Gen , Humanos , Masculino , Datos de Secuencia Molecular , Metástasis de la Neoplasia , Linaje , Feocromocitoma/diagnóstico por imagen , Feocromocitoma/patología , Cintigrafía , Somatostatina/análogos & derivadosRESUMEN
RET mutations play an important role in the development of human neuroendocrine tumors. The prevalence of the RET polymorphism G691S of exon 11 is higher in patients with medullary thyroid carcinoma (MTC) as compared to the general population. A weak association between RET polymorphisms and sporadic papillary thyroid carcinoma (PTC) has also been described. We hereby describe the association of MTC, bronchial carcinoid tumor, and PTC in a familial setting. A 75-yr-old woman developed MTC 7 yr after successful treatment of a bronchial carcinoid. Serum calcitonin was 12.9 pg/ml with a peak response to pentagastrin (151.0 pg/ml). The patient underwent total thyroidectomy and a genetic mutational analysis of the RET gene. Histological evaluation confirmed MTC with no evidence of lymph nodes involvement. After thyroidectomy serum calcitonin was <2.0 pg/ml. A germline missense mutation at codon 691 in exon 11 of the RET gene was found. The mutational analysis was extended to the patient's offspring, and her daughter was found to bear the G691S polymorphism of RET. Wild type RET gene was found in the son. The daughter, who showed a nodular goiter, autoimmune thyroiditis and normal serum calcitonin, also underwent thyroidectomy. Histologic examination of the thyroid revealed an incidental PTC. This is the first description of a bronchial carcinoid tumor occurring in association with MTC. The occurrence of apparently unrelated NET in the same subject, or within a family, should be regarded as a challenge for deeper investigations into the possible oncogenic role of this genetic alteration.
Asunto(s)
Neoplasias de los Bronquios/genética , Tumor Carcinoide/genética , Carcinoma Medular/genética , Carcinoma Papilar/genética , Neoplasias de Tejido Vascular/genética , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Adulto , Anciano , Secuencia de Bases , Análisis Mutacional de ADN , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Mutación Missense , Linaje , Polimorfismo GenéticoRESUMEN
CONTEXT: Medullary thyroid carcinoma (MTC) is the most common feature of multiple endocrine neoplasia type 2A (MEN2A) and occurs in almost all patients affected by germline RET mutations. OBJECTIVE: We identified and characterized an activating germline RET point mutation (G>A substitution leading to the heterozygous missense mutation Y606C in exon 10), in a 58-year-old female affected by MTC. DESIGN: The RET/Y606C and RET/C620Y, obtained by site-directed mutagenesis, as well as the RET/wild-type (wt) were cloned in an expression vector and transiently transfected in NIH3T3 fibroblasts. In vitro cell model was used to evaluate the effect of Y606C mutation on the RET downstream signalling pathways through Western blot analysis. RESULTS: We found that the cysteine insertion, due to the Y606C mutation, results in increased receptor dimerization, which is accompanied by an increased tyrosine phosphorylation of the Y905 residue in the RET/Y606C, demonstrating that the Y606C mutation is associated with constitutive receptor activation. As RET activation results in an intracellular signalling cascade involving extracellular signal-regulated kinases (ERKs), we investigated ERK activity in our transfected cells. Results demonstrated a significant increase in ERK2 phosphorylation in the RET/Y606C vs. the RET/wt and RET/C620Y transfected cells, suggesting an up-regulation of RET signalling. CONCLUSIONS: All these findings demonstrate that the Y606C mutation is associated with RET constitutive activation and thus has to be considered of pathogenetic relevance in the development of MTC.
Asunto(s)
Mutación de Línea Germinal , Proteínas Proto-Oncogénicas c-ret/genética , Proteínas Proto-Oncogénicas c-ret/fisiología , Sustitución de Aminoácidos/genética , Animales , Secuencia de Bases , Carcinoma Medular/complicaciones , Carcinoma Medular/genética , Cisteína/genética , Femenino , Humanos , Ratones , Persona de Mediana Edad , Neoplasia Endocrina Múltiple Tipo 2a/complicaciones , Neoplasia Endocrina Múltiple Tipo 2a/genética , Células 3T3 NIH , Neoplasias de la Tiroides/complicaciones , Neoplasias de la Tiroides/genética , Tirosina/genéticaRESUMEN
PGL3 syndrome is caused by mutations in the SDHC gene. At present, only a few families affected by SDHC mutations have been reported in the literature and in each of them the clinical presentation was characterised by paragangliomas located only in the head and neck regions. No evidence of thoracic or abdominal catecholamine-secreting chromaffin tumours has been reported to date. We report the case of a 15-year-old girl with hypertension and a norepinephrine-secreting abdominal paraganglioma who was found to harbour a novel nonsense SDHC mutation, demonstrating that the clinical presentation of PGL3 syndrome can be more diverse than expected.
Asunto(s)
Neoplasias Abdominales/genética , Pruebas Genéticas , Proteínas de la Membrana/genética , Síndromes Neoplásicos Hereditarios/genética , Paraganglioma/genética , Feocromocitoma/genética , Neoplasias Abdominales/diagnóstico , Adolescente , Codón sin Sentido , Femenino , Humanos , Hipertensión/etiología , Proteínas de la Membrana/deficiencia , Síndromes Neoplásicos Hereditarios/diagnóstico , Especificidad de Órganos , Paraganglioma/diagnóstico , Feocromocitoma/diagnóstico , Mutación PuntualRESUMEN
The familial forms of pheochromocytoma have recently been demonstrated to be more frequent than believed in the past. The genes currently known to be responsible for tumor formation are RET, VHL, NF1, SDHB, SDHC and SDHD. Germline mutations of these genes increase the risk of developing pheochromocytomas and/or paragangliomas which variably associate with other neoplasms and characterize diverse clinical syndromes such as MEN 2, von Hippel-Lindau (VHL), and neurofibromatosis type 1 (NF 1), or the PGL syndromes, respectively. Although the pathogenesis of pheochromocytoma/paraganglioma formation is still largely unknown, studies of the familial forms have started to uncover some pathways that favor tumor formation, such as activation of tyrosine-kinase, induction of hypoxia-inducible factors, activation of the oncogene Ras or reduced apoptosis. These studies have also demonstrated that various gene mutations can differently affect the biological characteristics of pheochromocytoma: for example, while the tumors are mostly adrenergic (epinephrine secreting) and episodically secreting in MEN 2, they are mostly noradrenergic (norepinephrine secreting) and continuously secreting in VHL. Biological variability can also be observed in the PGL syndromes where tumors develop in the head and neck and are parasympathetic in origin and non-secreting, or in the thorax and the abdomen, where they are sympathetic in origin and catecholamine secreting. Genetic testing in patients with pheochromocytomas or paragangliomas is, at present, strongly recommended and is mandatory in young patients or in cases of multiple or recurrent tumors. The clinical picture and the biological characteristics of the tumor may suggest the priority of the genes to be tested first.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Neoplasias de las Glándulas Suprarrenales/fisiopatología , Feocromocitoma/genética , Feocromocitoma/fisiopatología , Mapeo Cromosómico , Humanos , Cresta Neural/patología , Neurofibromina 1/genética , Succinato Deshidrogenasa/genéticaRESUMEN
Mutations in genes encoding mitochondrial succinate dehydrogenase (SDH) are frequently involved in the development of neural crest-derived (NCD) tumors, such as pheochromocytomas (PHEOs) or paragangliomas (PGLs). In this study we report the results of sequencing analysis in leukocyte DNA of patients affected by PHEO/PGL who turned out to be SDH mutation carriers. A nonsense germline heterozygous mutation (Q109X) was found in the exon 4 of the SDHD gene in the index cases of six unrelated families affected by PHEO/PGL. Haplotype analysis showed the presence of a founder effect. Affected patients showed high clinical variability, ranging from monolateral to bilateral glomus tumors, variably associated or not with PGLs or PHEOs. A novel missense SDHD variant, T112I, was also found in one of our families. A new missense G106D mutation, involving a highly conserved amino acid, was found in two sisters affected by bilateral glomus tumors. A P81L mutation associated with abdominal and head and neck PGL was detected in three families. A G12S variant of the SDHD gene was found in one patient affected by a PHEO. The finding of this variant in 3 of 100 control subjects suggests that it is a polymorphism and not a mutation. A novel IVS2-1G>T variant was found at intron 2 of SDHD gene in one patient affected by a glomus tumor. All the tumors associated with SDHD mutations were benign. Conversely, the only mutation we found in SDHB gene (IVS3+1G>A) was associated with a malignant PHEO.
Asunto(s)
Mutación de Línea Germinal , Paraganglioma/genética , Succinato Deshidrogenasa/genética , Secuencia de Aminoácidos , Animales , Heterocigoto , Humanos , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Succinato Deshidrogenasa/químicaRESUMEN
The association of pheochromocytoma (PHEO) and pregnancy is uncommon and life threatening for both the fetus and the mother. Early diagnosis and treatment is essential to decrease maternal and fetal mortality and to differentiate the disease from the more common pre-eclampsia. While medical treatment should be started immediately after diagnosis, the timing of surgical treatment is still debated. We describe the case of a 27-yr-old woman in the 18th week of pregnancy who showed a biochemical pattern typical of PHEO and, by imaging studies, 2 tumors with the same characteristics: the first localized on the right adrenal gland, the second at the right renal hilum. The patient underwent surgery because of suspicion of malignant PHEO with local metastasis, while histology revealed a rare association of a solitary PHEO and para-aortic neurofibroma, both tumors embryologically deriving from a common cell precursor.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/complicaciones , Neurofibroma/complicaciones , Cuerpos Paraaórticos/patología , Feocromocitoma/complicaciones , Complicaciones Neoplásicas del Embarazo/diagnóstico , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Femenino , Humanos , Neurofibroma/diagnóstico , Feocromocitoma/diagnóstico , EmbarazoRESUMEN
Pituitary adenomas may be the cause of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), although few cases have so far been reported. We described a case of hypotonic hyponatremia in a 76-yr-old man with a pituitary macroadenoma. He had a recent history of two syncopal attacks which had occurred in the last two months. Baseline assessment demonstrated a sodium serum level of 114 mEq/l. Clinically, the patient appeared euvolemic. Thyroid and adrenal function testing did not show any abnormality. Plasma and urinary osmolality (238 and 186 mOsm/kg, respectively) were in agreement with the diagnosis of SIADH. Accordingly, 3% hypertonic saline solution was started, followed by water intake restriction when natremia reached 126 mEq/l. A computed tomography (CT) scan of the chest revealed the presence of a 2-cm lesion in the azygos-esophageal recess. Because the nature of the lesion appeared uncertain, antibiotic therapy was initiated. After one month, a new CT scan did not show any evidence of the mediastinic mass. Sodium serum level was within the normal range (141 mEq/l) and remained stable thereafter, without fluid restriction. This case very well demonstrates that, in the presence of hyponatremia due to SIADH, more frequently associated co-morbidities (ie mediastinic diseases) have to be searched, even in the presence of a possible, yet rare, cause of this syndrome (ie pituitary adenoma).