Apoplexy in sporadic pituitary adenomas: a single referral center experience and AIP mutation analysis

ABSTRACT Objective: To analyze the clinical, laboratory, and radiological findings and management of patients with clinical pituitary apoplexy and to screen for aryl hydrocarbon receptor-interacting protein (AIP) mutations. Subjects and methods: The clinical findings were collected from the medical records of consecutive sporadic pituitary adenoma patients with clinical apoplexy. Possible precipitating factors, laboratory data, magnetic resonance imaging (MRI) findings and treatment were also analyzed. Peripheral blood samples were obtained for DNA extraction from leukocytes, and the entire AIP coding region was sequenced. Results: Thirty-five patients with pituitary adenoma were included, and 23 (67%) had non-functioning pituitary adenomas. Headache was observed in 31 (89%) patients. No clear precipitating factor was identified. Hypopituitarism was observed in 14 (40%) patients. MRI from 20 patients was analyzed, and 10 (50%) maintained a hyperintense signal in MRI performed more than three weeks after pituitary apoplexy (PA). Surgery was performed in ten (28%) patients, and 25 (72%) were treated conservatively with good outcomes. No AIP mutation was found in this cohort. Conclusion: Patients with stable neuroophthalmological impairments can be treated conservatively if no significant visual loss is present. Our radiological findings suggest that hematoma absorption lasts more than that observed in other parts of the brain. Additionally, our study suggests no benefits of AIP mutation screening in sporadic patients with apoplexy.

Proteína moduladora de la actividad del receptor de aril hidrocarburos (AIP): genética, bioquímica e impacto clínico / Aryl hydrocarbon receptor interacting protein (AIP): genetics, biochemistry and clinical impact

El gen AIP (proteína moduladora de la actividad del receptor de aril hidrocarburos) se localiza en la región 11q13.2 y codifica para una proteína de 330 aminoácidos que interactúa con el factor de transcripción AhR (receptor para aril hidrocarburos). Las mutaciones en este gen se han asociado con adenomas pituitarios aislados de tipo familiar (APAF). Se caracterizan por una presentación temprana (alrededor de 20 años), por lo regular producen hormona de crecimiento y/o prolactina, tienen un comportamiento clínico agresivo y poca respuesta a análogos de somatostatina.

The AIP gene (aryl hydrocarbon receptor interacting protein) is located on chromosome 11q13.2 and encodes a 330 amino acid protein which interacts with the aryl hydrocarbon receptor (AHR) transcription factor. Mutations in the AIP gene have been associated with familial isolated pituitary adenomas (FIPA). They characterize by an early-onset (around the age of 20 years old) and for being aggressive, growth hormone and/or prolactin-secreting tumors, with poor response to somatostatin analogues.

Estudios clínicos y genéticos en tres miembros de una familia afectados con adenomas hipofisarios aislados con prolactinomas homogéneos / Clinical and genetic studies of a three-member familial isolated pituitary adenoma with homogeneous prolactinomas

La mayoría de los adenomas hipofisarios son esporádicos, pero un 3-5% puede ocurrir en un contexto familiar y hereditario. Este es el caso de la neoplasia endocrina múltiple de tipo 1 (NEM1), complejo de Carney (CNC) y adenomas hipofisarios aislados familiares (FIPA). El FIPA es una condición infrecuente, que ocurre en un contexto familiar, no asociada a NEM t ipo1 ni CNC. Los FIPA pueden ser homogéneos (todos los adenomas tienen el mismo fenotipo) o heterogéneos (diferente fenotipo tumoral). Describimos una familia congolesa en la que dos hermanas y una prima fueron diagnosticadas a los 29, 32 y 40 años, respectivamente, con un prolactinoma (FIPA homogéneo). Las pacientes presentaron macroadenomas no invasivos al momento del diagnóstico, con buena respuesta biológica y tumoral al tratamiento con cabergolina hasta una dosis máxima de 1.5 mg/semanal. De las dos hermanas, una cursó un embarazo sin complicaciones. Durante el seguimiento de 12 años, ninguna de ellas presentó elementos clínicos o biológicos compatibles con NEM1 o CNC, por lo que dichos genes no se estudiaron. El análisis genético en dos de las pacientes permitió descartar la posibilidad de una mutación germinal del gen aryl hydrocarbon receptor interacting protein (AIP). Se considera que el 80% de los pacientes con FIPA no presentan mutación del gen AIP, por lo que se requieren futuros estudios en este tipo de familias, para poder determinar otros genes afectados involucrados en su fisiopatología.

Most pituitary adenomas are sporadic, but 3-5% can occur in a family and hereditary context. This is the case of multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC) and familial isolated pituitary adenomas (FIPA). FIPA is an infrequent condition that occurs in a family context, not associated with MEN type1 or CNC. FIPA kindred can be homogeneous (all adenomas affected in the family having the same tumor phenotype) or heterogeneous (different tumor phenotypes in the affected members). We describe a Congolese family in which two sisters and a cousin were diagnosed with a prolactinoma (homogenous FIPA) at the ages of 29, 32 and 40 years, respectively. The patients presented with macroadenomas at the time of diagnosis, non-invasive tumors and good biological response to cabergoline treatment (maximum dose of 1.5 mg/weekly). Of these two sisters, one went through a pregnancy without complications. Because no MEN1 and CNC clinical and biochemical features were detected during the 12-year follow-up, these genes were not investigated. The genetic analysis of the aryl hydrocarbon receptor interacting protein (AIP) was normal. As nearly 80% of patients with FIPA do not have a mutation in the AIP gene, future studies in these families are required to identify other affected genes involved in their physiopathology.

EIF1AX c.338-2A>T splice site mutation in a patient with trabecular adenoma and cytological indeterminate lesion

SUMMARY The EIF1AX gene mutations have been recently associated with papillary thyroid carcinoma and anaplastic thyroid cancer. According with these reports, the gene as been considered as a drive gene for thyroid cancer development. However, the occurrence of these alterations in benign thyroid lesions is not known and is still under investigation. Some authors have already reported the presence of EIF1AX variants in follicular adenomas and hyperplastic nodules. Here, we describe for the first time a case of a man with the EIF1AX c.338-2A>T splice site mutation in an indeterminate FNA lesion with trabecular adenoma at final histology in the absence of other pathogenetic mutations, demonstrating that further studies are required to better understand EIF1AX role in the tumorigenesis of thyroid carcinoma.

Hereditary pituitary tumor syndromes: genetic and clinical aspects

ABSTRACT The pituitary gland is responsible for the synthesis and secretion of various hormones that play a key role in regulating endocrine function and homeostasis. Pituitary adenomas (PA) are benign epithelial tumors arising from the endocrine cells of the anterior pituitary gland. Clinically relevant PA are relatively common and they occur in 0.1% of the general population. They are mostly benign monoclonal neoplasms that arise from any of the five hormone-secreting cell types of the anterior pituitary gland. PA are categorized as either functioning or non-functioning, depending on whether or not they produce a hormonal hypersecretion syndrome. Both functioning and non-functioning adenomas can produce symptoms or signs resulting from compression of the optic chiasm or invasion of cavernous sinuses. Only 5% of PA occur within the context of hereditary syndromes with reasonably well-defined oncogenic mechanisms. The vast majority of PA are sporadic, and their etiopathogenesis remains largely unknown. Pituitary tumor oncogenesis involves several mechanisms that eventually lead to abnormal cell proliferation and dysregulated hormone production. Among these factors, we found inactivating mutations of tumor suppressor genes, activating mutation of oncogenes and the participation of hormonal signals coming from the hypothalamus, all resulting in cell-cycle regulation abnormalities. In this review, we summarize the clinical and pathophysiological aspects of the different hereditary pituitary tumor syndromes.

Effect of lncRNA HULC knockdown on rat secreting pituitary adenoma GH3 cells

Pituitary adenoma is one of the most common tumors in the neuroendocrine system. This study investigated the effects of long non-coding RNAs (lncRNAs) highly up-regulated in liver cancer (HULC) on rat secreting pituitary adenoma GH3 cell viability, migration, invasion, apoptosis, and hormone secretion, as well as the underlying potential mechanisms. Cell transfection and qRT-PCR were used to change and measure the expression levels of HULC, miR-130b, and FOXM1. Cell viability, migration, invasion, and apoptosis were assessed using trypan blue staining assay, MTT assay, two-chamber transwell assay, Guava Nexin assay, and western blotting. The concentrations of prolactin (PRL) and growth hormone (GH) in culture supernatant of GH3 cells were assessed using ELISA. The targeting relationship between miR-130b and FOXM1 was verified using dual luciferase activity. Finally, the expression levels of key factors involved in PI3K/AKT/mTOR and JAK1/STAT3 pathways were evaluated using western blotting. We found that HULC was highly expressed in GH3 cells. Overexpression of HULC promoted GH3 cell viability, migration, invasion, PRL and GH secretion, as well as activated PI3K/AKT/mTOR and JAK1/STAT3 pathways. Knockdown of HULC had opposite effects and induced cell apoptosis. HULC negatively regulated the expression of miR-130b, and miR-130b participated in the effects of HULC on GH3 cells. FOXM1 was a target gene of miR-130b, which was involved in the regulation of GH3 cell viability, migration, invasion, and apoptosis, as well as PI3K/AKT/mTOR and JAK1/STAT3 pathways. In conclusion, HULC tumor-promoting roles in secreting pituitary adenoma might be via down-regulating miR-130b, up-regulating FOXM1, and activating PI3K/AKT/mTOR and JAK1/STAT3 pathways.

Study of major genetic factors involved in pituitary tumorigenesis and their impact on clinical and biological characteristics of sporadic somatotropinomas and non-functioning pituitary adenomas

Genetic and functional aberrations of guanine nucleotide-binding protein, alpha stimulating (GNAS), aryl hydrocarbon receptor interacting protein (AIP), and pituitary tumor transforming gene (PTTG) are among the most prominent events in pituitary tumorigenesis. A cohort of Brazilian patients with somatotropinomas (n=41) and non-functioning pituitary adenomas (NFPA, n=21) from a single tertiary-referral center were evaluated for GNAS and AIP mutations and gene expression of AIP and PTTG. Results were compared to the clinical and biological (Ki67 and p53 expression) characteristics of tumors and their response to therapy, if applicable. Genetic analysis revealed that 27% of somatotropinomas and 4.8% of NFPA harbored GNAS mutations (P=0.05). However, no differences were observed in clinical characteristics, tumor extension, response to somatostatin analog therapy, hormonal/surgical remission rates, Ki67 index, and p53 expression between mutated and non-mutated somatotropinomas patients. PTTG overexpression (RQ mean=10.6, min=4.39, max=11.9) and AIP underexpression (RQ mean=0.56, min=0.46-max=0.92) were found in virtually all cases without a statistically significant relationship with clinical and biological tumor features. No patients exhibited somatic or germline pathogenic AIP mutations. In conclusion, mutations in GNAS and abnormal PTTG and AIP expression had no impact on tumor features and treatment outcomes in this cohort. Our data support some previous studies and point to the need for further investigations, probably involving epigenetic and transcriptome analysis, to improve our understanding of pituitary tumor behavior.

Expression of E-cadherin, Slug and NCAM and its relationship to tumor invasiveness in patients with acromegaly

Pituitary adenomas account for 10-15% of primary intracranial tumors. Growth hormone (GH)-secreting adenomas account for 13% of all pituitary adenomas and cause acromegaly. These tumors can be aggressive, invade surrounding structures and are highly recurrent. The objective of this study was to evaluate E-cadherin, Slug and neural cell adhesion molecule (NCAM) expression in GH-secreting pituitary adenomas and its relationship to tumor invasiveness. A cross-sectional study of patients who underwent hypophysectomy due to GH-secreting pituitary adenoma from April 2007 to December 2014 was carried out. The medical records were reviewed to collect clinical data. Immediately after surgery, tumor samples were frozen in liquid nitrogen and stored in a biofreezer at -80°C for assessment of E-cadherin 1 (CDH1), SLUG (SNAI2), and NCAM (NCAM1) by real-time PCR. The samples were fixed in formalin and embedded in paraffin for immunohistochemical analysis of E-cadherin and NCAM. Thirty-five patients with acromegaly were included in the study. Of these, 65.7% had invasive tumors. Immunohistochemically, E-cadherin was expressed in 96.7% of patients, and NCAM in 80% of patients. There was no statistically significant relationship between tumor grade or invasiveness and immunohistochemical expression of these markers. Regarding gene expression, 50% of cases expressed CDH1, none expressed SNAI2, and 53.3% expressed NCAM1. There was no statistically significant relationship between tumor grade or invasiveness and gene expression of CDH1, SNAI2, and NCAM1. The absence of Slug overexpression and of E-cadherin and NCAM suppression suggests that expression of these markers is not associated with tumor invasiveness in GH-secreting pituitary adenomas.

Benchmarking pathway interaction network for colorectal cancer to identify dysregulated pathways

Different pathways act synergistically to participate in many biological processes. Thus, the purpose of our study was to extract dysregulated pathways to investigate the pathogenesis of colorectal cancer (CRC) based on the functional dependency among pathways. Protein-protein interaction (PPI) information and pathway data were retrieved from STRING and Reactome databases, respectively. After genes were aligned to the pathways, each pathway activity was calculated using the principal component analysis (PCA) method, and the seed pathway was discovered. Subsequently, we constructed the pathway interaction network (PIN), where each node represented a biological pathway based on gene expression profile, PPI data, as well as pathways. Dysregulated pathways were then selected from the PIN according to classification performance and seed pathway. A PIN including 11,960 interactions was constructed to identify dysregulated pathways. Interestingly, the interaction of mRNA splicing and mRNA splicing-major pathway had the highest score of 719.8167. Maximum change of the activity score between CRC and normal samples appeared in the pathway of DNA replication, which was selected as the seed pathway. Starting with this seed pathway, a pathway set containing 30 dysregulated pathways was obtained with an area under the curve score of 0.8598. The pathway of mRNA splicing, mRNA splicing-major pathway, and RNA polymerase I had the maximum genes of 107. Moreover, we found that these 30 pathways had crosstalks with each other. The results suggest that these dysregulated pathways might be used as biomarkers to diagnose CRC.

Microsatellite Instability of Gastric and Colorectal Cancers as a Predictor of Synchronous Gastric or Colorectal Neoplasms

BACKGROUND/AIMS: Microsatellite instability (MSI) plays a crucial role in gastrointestinal carcinogenesis. The aim of this study was to clarify whether MSI is a useful marker for predicting synchronous gastric and colorectal neoplasms. METHODS: Consecutive patients who underwent both esophagogastroduodenoscopy and colonoscopy before the resection of gastric or colorectal cancers were included. MSI was analyzed using two mononucleotide and three dinucleotide markers. RESULTS: In total, 434 gastric cancers (372 microsatellite stability [MSS], 21 low incidence of MSI [MSI-L], and 41 high incidence of MSI [MSI-H]) and 162 colorectal cancers (138 MSS, 9 MSI-L, and 15 MSI-H) were included. Patients with MSI gastric cancer had a higher prevalence of synchronous colorectal cancer, colorectal adenoma, and gastric adenoma than those with MSS gastric cancers (4.8% vs 0.5%, p=0.023; 11.3% vs 3.2%, p=0.011; 3.2% vs 1.2%, p=0.00, respectively). The prevalence of synchronous colorectal adenomas was highest in MSI-L gastric cancers (19.0%), compared with MSI-H (7.3%) or MSS (3.2%) gastric cancers (p=0.002). In addition, there were no significant differences in the prevalence rates of synchronous colorectal adenoma among the MSI-H (13.3%), MSI-L (11.1%), and MSS (12.3%) colorectal cancers (p=0.987). CONCLUSIONS: The presence of MSI in gastric cancer may be a predictor of synchronous gastric and colorectal neoplasms, whereas MSI in colorectal cancer is not a predictor of synchronous colorectal adenoma.

Serological under expression of microRNA-21, microRNA-34a and microRNA-126 in colorectal cancer

PURPOSE: This paper describes the ability of miRNA value predict oncological outcomes in CRC patients and correlates to clinical and pathologic variables. METHODS: We prospectively analyzed the serological expression of microRNA-21, microRNA-34a, and microRNA-126 in 37 stage II - IV CRC patients and correlate to seven fit counterparts. Serological microRNAs were extracted using the miRNeasy Mini Kit(r) (Qiagen, Hilden, Germany). Quantification of microRNAs was performed using TaqMan Master Mix(r) reagent (Applied Biosystems, USA). RESULTS: We obtained serological underexpression microRNA-21, microRNA-34a, and microRNA-126 in CRC group. However, miRNAs serological values do not impact prognosis. Furthermore, miRNAs was not influenced by CEA values, TNM staging, and histological subtype. CONCLUSION: Despite lower expression of miR-21, miR-34a and miR-126 in the CRC group, no association with poor prognosis was found.

Carga de doença no Brasil: um olhar sobre o álcool e a cirrose não viral / Disease burden in Brazil: an investigation into alcohol and non-viral cirrhosis

O uso/dependência de álcool é importante fator de risco para o desenvolvimento da cirrose. O objetivo deste artigo é descrever e analisar o DALY (Disability Adjusted Life Years), o YLL (Years of Life Lost) e o YLD (Years Lived with Disability) de uso/dependência de álcool e da cirrose de etiologia não viral no Brasil, em 2008. O DALY foi calculado pela soma do YLL e do YLD. Para o YLL, foi utilizada a média dos óbitos de 2007-2009 no país. Através da revisão de dados epidemiológicos e do uso da ferramenta DisMod, a prevalência de cada um dos agravos foi modelada, gerando dados de incidência para o cálculo do YLD. O álcool e a cirrose foram responsáveis, respectivamente, por 3% e 1% do DALY total. Considerando-se as dez primeiras causas de DALY para homens, o uso/ dependência de álcool ocupou a segunda, terceira e sexta posições nas idades de 15-29, 30-44 e 45-59 anos, respectivamente. A cirrose ocupou a oitava posição no grupo de 30-44 anos; a quinta, no de 45-59 e a oitava, no de 60-69. A distribuição dos agravos por faixa etária sugere que intervenções direcionadas ao uso/dependência de álcool terão efeitos na carga de cirrose alcoólica no país.

Alcohol use/dependence are an important risk factor for cirrhosis of the liver. The article aims to describe and conduct a comparative analysis of Disability Adjusted Life Years (DALY), Years of Life Lost (YLL) and Years Lived with Disability (YLD) of alcohol use disorders and non-viral cirrhosis in Brazil in 2008. DALY was calculated as the sum of YLL and YLD. For YLL estimates, the mean number of deaths from 2007- 2009 in the country was considered. After revision of epidemiological data, prevalence of each disease was modelled with the DisMod tool, which generated incidence data for YLD estimates. Alcohol and non-viral cirrhosis were responsible for 3% and 1% of total DALYs, respectively. In both diseases, men contributed to a greater proportion of DALYs. Among the first ten causes of DALYs, alcohol use disorders occupied the second, third and sixth positions at the ages of 15-29, 30-44 and 45- 59, respectively. Non-viral cirrhosis was the eighth cause of DALY in the 30-44 age group in men; the fifth, in the 45-59 group and the eighth, in the 60-69 group. Age distribution suggests that interventions directed against alcohol use/dependence would have effects on the burden of alcoholic cirrhosis in the country.

Forty years of a psychiatric day hospital / Quarenta anos de um hospital de dia de psiquiatria

INTRODUCTION: Day hospitals in psychiatry are a major alternative to inpatient care today, acting as key components of community and social psychiatry. Objective: To study trends in the use of psychiatric day hospitals over the last decades of the 20th century and the first decade of the 21st century, focusing on patient age, sex, and diagnostic group, using data from Centro Hospitalar São João, Porto, Portugal. METHODS: Data corresponding to years 1970 to 2009 were collected from patient files. Patients were classified into seven diagnostic groups considering their primary diagnoses only. RESULTS: Mean age upon admission rose from 32.7±12.1 years in the second half of the 1970s to 43.5±12.2 years in 2005-2009 (p for trend < 0.001). Most patients were female (63.2%), however their proportion decreased from nearly 70% in the 1970s to 60% in the first decade of the 21st century. In males, until the late 1980s, neurotic disorders (E) were the most common diagnosis, accounting for more than one third of admissions. In the subsequent years, this proportion decreased, and the number of admissions for schizophrenia (C) exceeded 50% in 2004- 2009. In females, until the late 1980s, affective disorders (D) and neurotic disorders (E), similarly distributed, accounted for most admissions. From the 1990s on, the proportion of neurotic disorders (E) substantially decreased, and affective disorders (D) came to represent more than 50% of all admissions. CONCLUSIONS: Mean age upon admission rose with time, as did the percentage of female admissions, even though the latter tendency weakened in the last 10 years assessed. There was also an increase in the proportion of patients with schizophrenia. .

INTRODUÇÃO: Os hospitais de dia em psiquiatria representam atualmente uma das principais alternativas ao internamento, atuando como componentes chave na psiquiatria comunitária e social. OBJETIVO: Avaliar tendências na utilização de um hospital de dia no período compreendido entre as últimas décadas do século 20 e a primeira década do século 21, com foco em idade, sexo e grupo diagnóstico, usando dados do Centro Hospitalar São João, Porto, Portugal. MÉTODOS: Dados correspondentes aos anos 1970 a 2009 foram coletados dos prontuários clínicos. Os pacientes foram classificados em sete grupos diagnósticos, tendo em conta o diagnóstico principal. Resultados: A idade média na admissão aumentou de 32.7±12.1 anos na segunda metade da década de 1970 para 43.5±12.2 anos em 2005-2009 (p < 0.001). A maioria dos pacientes era do sexo feminino (63.2%), no entanto sua proporção diminuiu de cerca de 70% na década de 1970 para 60% na primeira década do século 21. Nos homens, até o final dos anos 1980, o grupo das perturbações neuróticas (E) era o diagnóstico mais comum, representando mais de um terço das admissões. Durante os anos seguintes, essa proporção diminuiu, e o número de admissões por esquizofrenia (C) alcançou mais de 50% no período de 2004-2009. Nas mulheres, até o final dos anos 1980, as perturbações afetivas (D) e as perturbações neuróticas (E), distribuídas similarmente, respondiam pela maioria das admissões. A partir dos anos 1990, a proporção das perturbações neuróticas (E) diminuiu substancialmente, e as perturbações afetivas (D) passaram a corresponder a mais de 50% do total das admissões. Conclusões: A idade média na admissão ...

Immunohistochemical analysis of thyroid follicular neoplasms and BRAF mutation correlation.

BACKGROUND: The accurate diagnosis of benign and malign thyroid tumors is very important for the clinical management of patients. The distinction of thyroid papillary carcinoma follicular variant and follicular adenoma can be difficult. AIM: To investigate the alternative methods like immunohistochemistry and exon 15 in the BRAF gene 1799 T/A mutation analyses for distinguishing thyroid tumors. MATERIALS AND METHODS: We applied immunohistochemical markers; CK19, HMWCK, Galectin‑3, HBME‑1 and Fibronectin and mutant allelespecific PCR amplification technique was used to determine 1799 T/A mutation within the BRAF gene. Formalin‑fixed parafin embedded tissues from 45 surgically total resected thyroids, included 26 thyroid papillary carcinoma follicular variant (FV‑TPC), 8 Follicular Adenoma (FA), 6 Minimal invasive follicular carcinoma (MIFC) and 5 Follicular Carcinoma (FC). STATISTICAL ANALYSES USED: Pearson Chi‑Square and Kruskal Wallis tests were performed. RESULTS: There was a positive correlation between FV‑TPC and HMWCK, CK 19, HBME1, Galectin 3, fibronectin (P < 0.05), but there was no correlation with FV‑TPC and BRAF gene mutation (P > 0.05). HBME‑1 and CK 19 stained strong and diffuse positive in FV‑TPCs but weak and focal in FAs. CONCLUSION: Our study suggests that morphologic features combined with immunohistochemical panel of HMWCK, CK19, HBME‑1, Galectin‑3 and fibronectin can help to distinguish benign and malign thyroid neoplasms and FV‑TPC from follicular adenomas. BRAF gene 1799 T/A mutation has been non‑specific but its detection can be a useful tool combined with immunohistochemistry for diagnosing FV‑TPC.

The Occurrence of Primary Hepatic Adenoma in Deceased Donor Renal Transplant Recipient

Main findings: We reported a case of new-onset, multi-focal hepatic adenoma in an 18 year-old man with no classic risk factors occurring forty months after a renal transplant from a cadaver donor. Histopathology of the adenoma was examined and genotype and phenotype were also analyzed. Histopathologic examination of the adenoma showed no malignancy. Genotype and phenotype analysis revealed no HNF1α or β-catenin gene mutations and no inflammatory infiltration. The patient was well and disease-free postoperatively. Case hypothesis: Hepatic adenoma occurs mostly in those taking oral contraceptives or androgenic-anabolic steroids or in those with hereditary diseases. Hepatic adenoma in a renal transplant recipient is rare and has only been reported in one case with glycogen storage disease type Ia. Immunosuppressive treatment might have contributed to the development of the neoplasm. Promising future implications: Although malignant change occurs most often in β-catenin gene mutation hepatic adenoma, surgical resection of the adenoma in a patient under immunosuppressive therapy should be considered in order to avoid the possibility of malignant transformation or hemorrhagic rupture. .

PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation

OBJECTIVE: The expression of transcription factors involved in early pituitary development, such as PROP1 and POU1F1, has been detected in pituitary adenoma tissues. In this study, we sought to characterize the transcriptional profiles of PROP1, POU1F1, and TBX19 in functioning and nonfunctioning pituitary adenomas in an attempt to identify their roles in tumorigenesis and hormone hypersecretion. METHODS: RT-qPCR analyses were performed to assess the transcriptional pattern of PROP1, POU1F1, TBX19, and hormone-producing genes in tissue samples of corticotrophinomas (n = 10), somatotrophinomas (n = 8), and nonfunctioning adenomas (n = 6). RESULTS: Compared with normal pituitary tissue, POU1F1 was overexpressed in somatotrophinomas by 3-fold. PROP1 expression was 18-fold higher in corticotrophinomas, 10-fold higher in somatotrophinomas, and 3-fold higher in nonfunctioning adenomas. TBX19 expression was 27-fold higher in corticotrophinomas. Additionally, the level of TBX19 mRNA positively correlated with that of pro-opiomelanocortin (r = 0.49, p = 0.014). CONCLUSIONS: Our data demonstrate that PROP1 is overexpressed in pituitary adenomas, mainly in corticotrophinomas. Together with previously published data showing that patients who harbor PROP1 loss-of-function mutations present a progressive decline in corticotrope function, our results support a role for PROP1 in pituitary tumor development and in the maintenance of cell lineages committed to corticotrophic differentiation. .

Immunohistochemical Expression of p53, Bcl-2, and Ki-67 Proteins in Traditional Serrated Adenomas of Colon / 대한소화기학회지

BACKGROUND/AIMS: Serrated adenomas of the colon show mixed characteristics of both hyperplastic and adenomatous polyps. Serrated adenomas are known to progress via the serrated pathway than the adenoma-carcinoma pathway. The aim of this study was to evaluate the characteristics of traditional serrated adenomas compared to hyperplastic polyps and tubular adenomas by using immunohistochemical staining for p53, Bcl-2, and Ki-67. METHODS: Age, sex, location, size and the immunoexpression of p53, Bcl-2, and Ki-67 were retrospectively analyzed in 20 traditional serrated adenomas, 20 hyperplastic polyps, and 20 tubular adenomas from January 2007 to December 2012 at The Catholic University of Korea, Yeouido St. Mary's Hospital. RESULTS: There was no difference in Bcl-2 and p53 expression between traditional serrated adenomas and hyperplastic polyps. Ki-67 Expression of traditional serrated adenomas was higher than that of hyperplastic polyps (p=0.001). Ki-67 and p53 expression was similar between traditional serrated and tubular adenomas. Bcl-2 expression of traditional serrated adenomas was lower than that of tubular adenomas (p=0.001). Regarding the expression of p53, Bcl-2, and Ki-67 in traditional serrated adenomas, there were no statistical differences among age, sex, location, and size. CONCLUSIONS: Our study suggested that Ki-67 may be helpful in distinguishing traditional serrated adenomas from hyperplastic polyps, and p53 expression may be ineffective in distinguishing between traditional serrated and tubular adenomas. From Bcl-2 expression, it is suggested that the tumorigenesis of traditional serrated adenomas is lower than that of tubular adenomas.

Immunohistochemical Expression of p53, Bcl-2, and Ki-67 Proteins in Traditional Serrated Adenomas of Colon / 대한소화기학회지

BACKGROUND/AIMS: Serrated adenomas of the colon show mixed characteristics of both hyperplastic and adenomatous polyps. Serrated adenomas are known to progress via the serrated pathway than the adenoma-carcinoma pathway. The aim of this study was to evaluate the characteristics of traditional serrated adenomas compared to hyperplastic polyps and tubular adenomas by using immunohistochemical staining for p53, Bcl-2, and Ki-67. METHODS: Age, sex, location, size and the immunoexpression of p53, Bcl-2, and Ki-67 were retrospectively analyzed in 20 traditional serrated adenomas, 20 hyperplastic polyps, and 20 tubular adenomas from January 2007 to December 2012 at The Catholic University of Korea, Yeouido St. Mary's Hospital. RESULTS: There was no difference in Bcl-2 and p53 expression between traditional serrated adenomas and hyperplastic polyps. Ki-67 Expression of traditional serrated adenomas was higher than that of hyperplastic polyps (p=0.001). Ki-67 and p53 expression was similar between traditional serrated and tubular adenomas. Bcl-2 expression of traditional serrated adenomas was lower than that of tubular adenomas (p=0.001). Regarding the expression of p53, Bcl-2, and Ki-67 in traditional serrated adenomas, there were no statistical differences among age, sex, location, and size. CONCLUSIONS: Our study suggested that Ki-67 may be helpful in distinguishing traditional serrated adenomas from hyperplastic polyps, and p53 expression may be ineffective in distinguishing between traditional serrated and tubular adenomas. From Bcl-2 expression, it is suggested that the tumorigenesis of traditional serrated adenomas is lower than that of tubular adenomas.

Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma / Estudos genéticos na coexistência de acromegalia, feocromocitoma, tumor do estroma gastrointestinal (GIST) e adenoma folicular de tireoide

We report on an adult woman with rare coexistence of acromegaly, pheochromocytoma (PHEO), gastrointestinal stromal tumor (GIST), intestinal polyposis, and thyroid follicular adenoma. At the age of 56, she was diagnosed with acromegaly caused by a pituitary macroadenoma, treated by transsphenoidal surgery, radiotherapy, and octreotide. During routine colonoscopy, multiple polyps were identified as tubular adenomas with high-grade dysplasia on histology. Years later, an abdominal mass of 8.0 x 6.2 cm was detected by routine ultrasound. Surgical exploration revealed an adrenal mass and another tumor adhered to the lesser gastric curvature, which were removed. Pathology confirmed the diagnosis of PHEO and GIST. PHEO immunohistochemistry was negative for GHRH. During follow-up, nodular goiter was found with normal levels of calcitonin and inconclusive cytology. Near-total thyroidectomy was performed, revealing a follicular adenoma. Her family history was negative for all of these tumor types. Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative. Though the finding of PHEO and acromegaly with multiple other tumors could be a fortuitous coexistence, we suggest that this case may represent a new variant of MEN syndrome with a de novo germline mutation in a not yet identified gene. Arq Bras Endocrinol Metab. 2012;56(8):507-12.

Relatamos o caso de uma mulher com rara coexistência de acromegalia, feocromocitoma (FEO), tumor do estroma gastrointestinal (GIST), polipose intestinal e adenoma folicular de tireoide. Aos 56 anos, ela foi diagnosticada com acromegalia por um macroadenoma hipofisário, tratado com cirurgia transesfenoidal, radioterapia e octreotide. Uma colonoscopia de rotina detectou múltiplos pólipos, que à histologia eram adenomas tubulares com alto grau de displasia. Anos mais tarde, uma ecografia detectou uma massa abdominal de 8.0 x 6.2 cm, que na exploração cirúrgica era uma lesão adrenal e outro tumor aderido à pequena curvatura gástrica. A patologia confirmou os diagnósticos de FEO e GIST. A imuno-histoquímica do FEO foi negativa para GHRH. No seguimento, encontrou-se um bócio nodular com níveis normais de calcitonina e citologia inconclusiva. Após tireoidectomia total o diagnóstico histológico foi de adenoma folicular. A história familiar era negativa para todos esses tumores. As análises genéticas para genes de síndromes de FEO/paragangliomas (SDH A-D, SDHAF2, RET, VHL, TMEM127 e MAX) e para hipofisárias (AIP, MEN1 e p27) foram todas negativas. Embora a presença de FEO e acromegalia com múltiplos outros tumores possa ser uma coexistência fortuita, acreditamos na possibilidade de uma nova variante de NEM com uma mutação germinativa de novo em um gene ainda não identificado Arq Bras Endocrinol Metab. 2012;56(8):507-12.

Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas

The tumorigenesis of pituitary adenomas is poorly understood. Mutations of the PIK3CA proto-oncogene, which encodes the p110-α catalytic subunit of PI3K, have been reported in various types of human cancers regarding the role of the gene in cell proliferation and survival through activation of the PI3K/Akt signaling pathway. Only one Chinese study described somatic mutations and amplification of the PIK3CA gene in a large series of pituitary adenomas. The aim of the present study was to determine genetic alterations of PIK3CA in a second series that consisted of 33 pituitary adenomas of different subtypes diagnosed by immunohistochemistry: 6 adrenocorticotropic hormone-secreting microadenomas, 5 growth hormone-secreting macroadenomas, 7 prolactin-secreting macroadenomas, and 15 nonfunctioning macroadenomas. Direct sequencing of exons 9 and 20 assessed by qPCR was employed to investigate the presence of mutations and genomic amplification defined as a copy number ≥4. Previously identified PIK3CA mutations (exon 20) were detected in four cases (12.1%). Interestingly, the Chinese study reported mutations only in invasive tumors, while we found a PIK3CA mutation in one noninvasive corticotroph microadenoma. PIK3CA amplification was observed in 21.2% (7/33) of the cases. This study demonstrates the presence of somatic mutations and amplifications of the PIK3CA gene in a second series of pituitary adenomas, corroborating the previously described involvement of the PI3K/Akt signaling pathway in the tumorigenic process of this gland.