Adrenocortical tumors associated with the TP53 p. R337H germline mutation can be identified during child-care consultations / Tumores adrenocorticais associados à mutação germinativa TP53 p. R337H podem ser identificados durante as consultas de puericultura

Abstract Objective: To evaluate the clinical features associated with adrenocortical hormone overexpression and familial cancer profiling as potential markers for early detection of adrenocortical tumors in children from South and Southeast Brazil. Methods: The clinical manifestations and anthropometric measurements of 103 children diagnosed with adrenocortical tumors were analyzed. Results: Between 1982 and 2011, 69 girls and 34 boys diagnosed with adrenocortical tumors were followed-up for a median time of 9.0 years (0-34 years). Signs of androgen overproduction alone (n = 75) or associated with cortisol (n = 18) were present in 90.3%. TP53 p.R337H mutation was found in 90.5% of patients. Stages I, II, III, and IV were observed in 45.6%, 27.2%, 19.4%, and 7.8% of patients, respectively. At diagnosis, there were no significant differences in height (p = 0.92) and weight (p = 0.22) among children with adrenocortical tumors, but children with virilization alone had significantly higher height-for-age Z-scores (0.92 ± 1.4) than children with hypercortisolism alone or combined (−0.32 ± 1,8; p = 0.03). The five-year overall survival was 76.7% (SD ± 4.2). Patients with advanced-stage disease had a significantly worse prognosis than those with limited disease (p < 0.001). During follow-up, ten of 55 p.R337H carrier parents developed cancer, whereas none of the 55 non-carriers did. Conclusions: Signs of adrenocortical hormone overproduction appear early, even in cases with early-stage. These signs can be identified at the physical examination and anthropometric measurements. In southern Brazil, pediatric adrenocortical tumor is a sentinel cancer for detecting families with germline p.R337H mutation in TP53 gene.

Resumo Objetivo: Avaliar as manifestações clínicas da hiperexpressão de hormônios do córtex da adrenal e câncer familiar como marcadores para a detecção precoce de tumores adrenocorticais em crianças do Sul e Sudeste do Brasil. Pacientes e métodos: Foram analisadas as manifestações clínicas e antropométricas de 103 crianças diagnosticadas com tumores adrenocorticais. Resultados: Entre 1982 e 2011, 69 meninas e 34 meninos diagnosticados com tumores adrenocorticais foram acompanhados por um tempo mediano de nove anos (0-34). Ao diagnóstico, sinais de virilização isolada (n = 75) ou associada ao cortisol (n = 18) estavam presentes em 90,3% dos pacientes; a mutação do gene TP53 p.R337H foi identificada em 90,5% dos pacientes. Os pacientes foram classificados em estádio I (45,6%), II (27,2%), III (19,4%) e IV (7,8%). Ao diagnóstico, não houve diferença significativa para as medidas de altura (p = 0,92) e de peso (p = 0,22) entre as crianças com tumores adrenocorticais, mas crianças com virilização tiveram escore-Z mais elevado para a idade (0,92 ± 1,4) do que aquelas com hipercortisolismo isolado ou combinado (−0,32 ± 1,8; p = 0,03). A sobrevida global de cinco anos foi de 76,7% (DP ± 4,2). Pacientes com estádios avançados tiveram pior prognóstico (p < 0,001). Durante o seguimento, 10 dos 55 genitores portadores da p.R337H desenvolveram câncer, enquanto que nenhum caso ocorreu entre os 55 não portadores. Conclusões: Os sinais de hiperprodução de hormônios adrenocorticais aparecem precocemente no desenvolvimento do tumor e podem ser identificados pelo exame físico e pelas medidas antropométricas na consulta pediátrica de rotina. O tumor adrenocortical pediátrico é sentinela para a detecção de câncer em famílias que segregam a mutação germinativa p.R337H do gene TP53.

New evidences on the regulation of SF-1 expression by POD1/TCF21 in adrenocortical tumor cells

OBJECTIVES: Transcription Factor 21 represses steroidogenic factor 1, a nuclear receptor required for gonadal development, sex determination and the regulation of adrenogonadal steroidogenesis. The aim of this study was to investigate whether silencing or overexpression of the gene Transcription Factor 21 could modulate the gene and protein expression of steroidogenic factor 1 in adrenocortical tumors. METHODS: We analyzed the gene expression of steroidogenic factor 1 using qPCR after silencing endogenous Transcription Factor 21 in pediatric adrenal adenoma-T7 cells through small interfering RNA. In addition, using overexpression of Transcription Factor 21 in human adrenocortical carcinoma cells, we analyzed the protein expression of steroidogenic factor 1 using Western blotting. RESULTS: Transcription Factor 21 knockdown increased the mRNA expression of steroidogenic factor 1 by 5.97-fold in pediatric adrenal adenoma-T7 cells. Additionally, Transcription Factor 21 overexpression inhibited the protein expression of steroidogenic factor 1 by 0.41-fold and 0.64-fold in two different adult adrenocortical carcinoma cell cultures, H295R and T36, respectively. CONCLUSIONS: Transcription Factor 21 is downregulated in adrenocortical carcinoma cells. Taken together, these findings support the hypothesis that Transcription Factor 21 is a regulator of steroidogenic factor 1 and is a tumor suppressor gene in pediatric and adult adrenocortical tumors.

Advance in diagnosis and treatment of adrenocortical tumor / 中华内分泌外科杂志

Management of adrenocortical tumor are developing vigorously,from diagnostic treatment to precisely therapy with endocrine lab test and radiology examination improving.The prevalence rate of incidental adrenal mass is 7％.Update researches show that surgical treatment is beneficial in subclinical hypercorisolism patients combined with adrenal incidentaloma.Histopathology improves the evaluation of prognosis in primary aldosteronism patients.For adrenocortical cancer patients,mitotane with combination of etoposide,doxorubicin and cisplatin after surgical treatment was recommended,while adjuvant radiotherapy needs more study to conform the efficacy.

Female sexual abnormality caused by androgen-producing adrenocortical adenoma：One case report / 中华内分泌代谢杂志

Objective To describe a case of female sexual abnormality with 46, XX caused by an androgen-producing adrenocortical tumor and to explore the mechanism of abnormal androgen secretion from the tumor. Methods The tumor tissues as the experimental group were compared with the normal adrenal tissue. The LH/human chorionic gonadotropin ( hCG) receptor was determined by immunohistochemisty, the activity of 3β-hydroxysteroid dehydrogenase ( 3β-HSD ) , 17α-hydroxylase ( CYP17 ) , and 17β-hydroxysteroid oxidoreductase ( 17β-HSD ) by enzyme linked immunosorbent assay(ELISA) and the expression of mRNA of 3β-HSD2, 17β-HSDB3, CYP17, and LH/hCG receptor by real-quantitative polymerase chain reaction ( RQ-PCR ) . Results The immunohistochemisty results showed that the LH/hCG receptor was negative in the experiment group, but positive in control. The activity of 3β-HSD and CYP17 of the experiment group was higher than that in the control (P<0. 01), while the activity of 17β-HSD was lower(2 638. 798±70. 551 vs 9 148. 174±382. 836, P<0. 01) according to ELISA results. The relative contentof3β-HSD2mRNAoftheexperimentgroupwashigherthanthatinthecontrol(P<0.05),andtherelative content CYP17 mRNA of the experiment group was much higher than that in the control (P<0. 01). However, the relative content of 17β-HSDB3 mRNA and LH/hCG receptor mRNA were much lower than those in the control ( P<0. 01) by RQ-PCR. Conclusion Sexual abnormality and virilization could be caused by the excessive androgen secreted by androgen-producing adrenocortical tumor, which is an extremely rare disease. The mechanism of the secretion of androgen from the tumor remains unknown so far. It may be related to the increased activity of 3β-HSD and CYP17, but has no relationship with the expression of LH/hCG receptor.

Etiology and clinical characteristics of 30 children with tumor-associated precocity / 中华实用儿科临床杂志

Objective To analyze the etiology and clinical characteristics of children with tumor-associated precocity.Methods Thirty children with tumor-associated precocity hospitalized in Department of Surgery of Beijing Children's Hospital Affiliated to Capital Medical University from Jan.2006 to Mar.2012 were selected as research subjects.The causes,clinical characteristics and treatment situation of the patients were retrospectively studied.Results The group of patients included 14 boys and 16 girls,with average age of (3.74 ± 2.44) years.Twenty-two patients (73.3％) were younger than 5 years old,and their etiological distributions listed as follows:8 cases were hypothalamic hamartoma(HH),2 cases were hypothalamic germinoma,1 case was arachnoid cyst,7 cases were adrenocortical tumor (in which 1 case was adenoma and 6 cases were adenocacinoma respectively),5 cases were ovarian cyst,2 cases were ovarian tumor (in which 1 case was endodermal sinus tumor and 1 case was sex cord-stromal tumor respectively),2 cases were MuCune-Albright syndrome,and 1 case was mediastinal teratoma,1 case was penis primitive neuroectoderm tumor,and 1 case was Leydig cell proliferation accompanied with neoplasma.Eleven patients(36.7％) suffered central precocious puberty,with HH (n =8) being the most common causes.Four patients with HH presented with gelastic epilepsy.Precocious puberty caused by HH patients could be safely controlled by gonadotropin-releasing hormone agonists.Nineteen patients(63.3％) suffered peripheral precocious puberty,with adrenocortical tumor being the most common cause for the boys and ovarian cyst being the most common cause for the girls.Besides that,the onset symptom of a patient with adenocacinoma was facial acne accompanied with hypertrichiasis and another patient with ovarian tumor had intermittent abdominal pain,and the onset symptoms of all the boys were external genital development and those of the girls were mammary development or colporrhagia,respectively.Conclusions Tumors are one of the most causes of precocious puberty in children.During the process of diagnosis and treatment of precocious puberty,imaging examinations on pituitary,gonad and adrenal gland should be paid great attention to and seldom occurred tumors should also be considered.For ovarian cyst patients with precocious puberty attention shall be paid attention to the differentiation from MuCune-Albright syndrome.

Genotype analysis of the human endostatin variant p.D104N in benign and malignant adrenocortical tumors

OBJECTIVE: Endostatin is a potent endogenous inhibitor of angiogenesis. It is derived from the proteolytic cleavage of collagen XVIII, which is encoded by the COL18A1 gene. A polymorphic COL18A1 allele encoding the functional polymorphism p.D104N impairs the activity of endostatin, resulting in a decreased ability to inhibit angiogenesis. This polymorphism has been previously analyzed in many types of cancer and has been considered a phenotype modulator in some benign and malignant tumors. However, these data are controversial, and different results have been reported for the same tumor types, such as prostate and breast cancer. The purpose of this study was to genotype the p.D104N variant in a cohort of pediatric and adult patients with adrenocortical tumors and to determine its possible association with the biological behavior of adrenocortical tumors. METHODS: DNA samples were obtained from 38 pediatric and 56 adult patients (0.6-75 yrs) with adrenocortical tumors. The DNA samples were obtained from peripheral blood, frozen tissue or paraffin-embedded tumor blocks when blood samples or fresh frozen tissue samples were unavailable. Restriction fragment length polymorphism analysis was used to genotype the patients and 150 controls. The potential associations of the p.D104N polymorphism with clinical and histopathological features and oncologic outcome (age of onset, tumor size, malignant tumor behavior, and clinical syndrome) were analyzed. RESULTS: Both the patient group and the control group were in Hardy-Weinberg equilibrium. The frequencies of the p.D104N polymorphism in the patient group were 81.9 percent (DD), 15.9 percent (DN) and 2.2 percent (NN). In the controls, these frequencies were 80.6 percent, 17.3 percent and 2.0 percent, respectively. We did not observe any association of this variant with clinical or histopathological features or oncologic outcome in our cohort of pediatric and adult patients with adrenocortical tumors.

Weiss criteria in large adrenocortical tumors: A validation study.

Background: Several systems including pathologic criteria alone or in combination with clinical features have been proposed to differentiate between benign and malignant adrenocortical tumors and assess their prognosis. The Weiss system appears to be the most commonly used method for assessing malignancy but there are only a few studies which have evaluated its diagnostic power. Since we see large adrenocortical carcinoma (ACC), we attempt to evaluate the diagnostic power of Weiss system in large ACC. Materials and Methods: In this study clinicopathological characteristics of 42 adrenocortical neoplasms are studied and classified into adrenocortical adenoma (ACA) and ACC based on Weiss score of less than or equal to three or greater than three. Results: The histological criteria of Weiss appeared to predict tumor prognosis accurately. Five year survival of patients with Weiss scores of less than or equal to three was 100% compared to 0% of those with Weiss scores greater than three. The average weights of ACA and ACC were 13.0 plus/minus 8.4 grams and 621.1 plus/minus 335.2 grams respectively; average sizes of ACA and ACC were 2.8 plus/minus 1.0 cmsand 13.6 plus/minus 3.7 cms respectively. Conclusion: Weiss score was found to be a good prognostic factor for tumors of the adrenal cortex.

Significance of expressions of Ki67 and FHIT in adrenocortical tumor tissue / 中华内分泌代谢杂志

The expressions of Ki67 and FHIT were detected by immunohistochemical staining in 15 cases of adrenocortical carcinoma, 42 cases with adrenocortical adenoma,6 cases of adrenocortical hyperplasia, and 10 cases of normal adrenocortical tissue. The results showed that the highest expression of Ki67 and the lowest expression of FHIT were found in adrenocortical carcinoma. There were significant differences in the Ki67 and FHIT between adrenocortical adenoma and adrenocortical carcinoma ( both P < 0. 05 ). There existed negative correlation between the expressions of Ki67 and FHIT( r=-0. 712, P<0.05 ). Ki67 over-expression and loss of FHIT expression may be involved in the occurrence and development of adrenocortical carcinoma. It is suggested that combined detections of Ki67 and FHIT may have reference significance in the differentiation of adrenocortical adenoma from adrenocortical carcinoma.

Isolated familial somatotropinoma: 11Q13-LOH and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis

OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.

Expression and significance of Ki67 and FHIT In adrenocortical tumor tissue / 中国综合临床

Objective To study relationship between Ki67 ,fragile histindine tried (FHIT) and adrenocortical tumors. Methods Ki67 and FHIT was detected by immunohistochemical staining in edrenecortical carcinoma(n=14) ,edrenocortical adenoma(n = 61) and normal adrenocortical tissue adjacent to tumor(n = 10). Results Ki67 was not expressed in normal adrenecortical tissue but highest expressed in adrenocortical carcinoma as well as in adrenocortical adenoma,and however,the expression of FHIT was expressed in a different way to Ki67. Negative correlation was observed between Ki67 and FHIT (r = -0.721 ,P <0.005). Conclusion The correlation of Ki67, FHIT with adrenocortical tumor, suggest that the detection of both Ki67 and FHIT can provide objective and simple diagnosis method to identify adrencortical adenomas from adrencortical carcinomas.

A case of adrenocortical adenoma following long-term treatment in a patient with congenital adrenal hyperplasia / 소아과

As a result of the widespread use and enhanced quality of high-resolution radiological techniques, a recent report has revealed a relatively high prevalence of small adrenal tumors in patients with untreated congenital adrenal hyperplasia due to 21-hydroxylase deficiency. However, there are scarcely any pediatric cases of adrenocortical tumor following long-term treatment in patients suffering with congenital adrenal hyperplasia. We report here on a pediatric female case of adrenocortical adenoma despite adequate long-term treatment for the salt-losing type of congenital adrenal hyperplasia.

Primary adrenocortical carcinoma: diagnosis and treatment / 中国医师进修杂志

Objective To improve the diagnosis and treatment of primary adrenocortical carcinoma. Methods Retrospective analysis was performed in clinical data of 16 patients with primary adrenocortical carcinoma. The diagnosis was based on clinical presentations,hormonal studies and imaging. Surgical treatment was underwent on 13 cases. All patients were followed up for 3 to 62 months. Results Of 16 cases,functional tumors were in 8,including Cushing′s syndrome in 5,combination of Cushing′s syndrome and virilization in 2,and hyperaldosteronism in 1. Imaging studies revealed the tumors were 4.8 to 19.5 cm in diameter,average in 7.8 cm. Distant metastasis occurred in 3 cases. Radical surgery was done in 13 cases without distant metastasis,including radical adrenalectomy in 8,adrenalectomy plus nephrectomy in 2,adrenalectomy plus surgical extirpation of intracaval tumor thrombus in 2,and partial resection of the wall of inferior vena cava in 1. Pathologic stages were stage Ⅰ in 2 cases,stage Ⅱ in 8,stage Ⅲ in 3,stage Ⅳ in 3. Among the 11 cases who were treated over 2 years after operation,6 cases were still survival,while 1 case had pulmonary and 1 case had bone metastasis. The other 5 cases survive in average of 26 months. Conclusions Prognosis of primary adrenocortical carcinoma is poor. The keys to early diagnosis are clinical manifestations plus imaging. Surgical treatment is the only effective therapy for the disease.