Outcomes following surgical management of adrenocortical carcinoma: A single-center experience. / Resultados del manejo quirúrgico del carcinoma adrenocortical: experiencia de un centro hospitalario.

OBJECTIVE: Adrenocortical carcinoma (ACC) is a rare and heterogeneous disease, with challenging management and poor prognosis. Surgery withcurative intent is the preferred treatment option for localized disease, with a reported 5-year survival rate of 55% for complete resections. However, owing to the high risk of recurrence there is a need for adjuvant therapies, such as mitotane, an adrenolytic drug, or irradiation, while in advanced disease the standard of careis a combined chemotherapy scheme. The aim of this study was to report our experience in the surgical management and outcomes of ACC patients. MATERIALS AND METHODS: A retrospective observational study was performed in a cohort of ACC patients who had undergone surgical resection (open or laparoscopic approach) and were followed up at our tertiary hospital. Patients with localized or locally advanced disease were included in the analysis. All medical records, including clinical, surgical, pathologic, and follow-updata, were collected and analyzed. RESULTS: A total of 19 ACC patients were managed at our center between August 1990 and August 2013. The median age at diagnosis was 50.5 years (range 19-72), and most patients were males. Abdominal pain was the most common clinical presentation (n=9,47.4%). Abdominal contrast-enhanced computed tomography (CT) was performed in all cases. Only 3 tumors (15.8%) were functional and most were stage II at diagnosis (n=9, 47.4%). No patient presented metastasis. Of the 19 patients, 18 (94.7%) under went surgerywith curative intent, while one (5.3%) received adjuvant radiotherapy (ART). The open approach was used in 17 patients (89.5%), while the remaining 2 (10.5%) underwent laparoscopy. Postoperative complications occurred in 8 patients (42.1%); none were of grade IV or V. Median follow-up was 66 months (range 3-312). The majority of patients (n=15, 78.9%) were disease free with surgery alone. None received adjuvant mitotane therapy (AMT). Four patients (21%) experienced metachronous metastases and 3 (15.8%) local recurrence after a median time of 10.5 months (range 2-60) and 9.3 months (range 1.5-30), respectively. The 5-year overall survival rate was 47.4%. CONCLUSIONS: Our findings confirm both the unpredictable nature of ACC and the accepted primary role of surgery. The use of adjuvant therapy was less frequent in this series than is supported currently. However, a multidiscipinary approach should be the initial step in the management of this rare malignancy.

OBJETIVO: El carcinoma adrenocortical es una enfermedad heterogénea y rara que conlleva un manejo complicado y cuyo pronóstico es malo. Ante una enefermedad localizada el manejo quirúrgico es de elección, observando una tasa de supervivencia a los 5 años del 55% en resecciones completas. Sin embargo, debido a la alta tasa de recurrencias, se requiere complementar el manejo con una terapia adyuvante como es el caso del mitotane, un agente adrenolítico, o la radioterapia. En casos de enfermedad avanzada la terapia de elección incluye una pauta de quimioterapia combinada. El objetivo del presente estudio es reportar nuestra experiencia en el manejo quirúrgico y resultados obtenidos de los pacientes con diagnóstico de carcinoma adrenocortical. MATERIALES Y MÉTODOS: Se realizó un estudio observacional de una cohorte de pacientes diagnosticados de carconinoma adrenocortical que requirieron un manejo quirúrgico (abierto o laparoscópico) y que realizaron su seguimiento en nuestro hospital terciario. Se incluyó a pacientes con enfermedad localizada y localmente avanzada en el análisis. Todos los dados clínicos, quirúrgicos, patológicos y de seguimiento fueron recolectados para el análisis. RESULTADOS: Entre agosto del 1990 y agosto del 2013 un total de 19 pacientes diagnosticados de carcinoma adrenocortical fueron tratados en nuestro centro. La mediana de edad al diagnóstico fue 50,5 años (rango 19-72), siendo la mayoría hombres. El síntoma inicial mas frecuente fue el dolor abdominal (n=9, 47,4%). Una tomografía computarizada con contraste fue realizada en todos los casos. Sólo 3 tumores (15,8%) eran funcionales y la mayoría correspondía a un estadio II al diagnóstico (n=9, 47,4%). Ningún paciente presentaba metástasis. De los 19 pacientes,18 (94,7%) requirieron cirugía con intención curativa, mientras que a uno (5,3%) se le realizó radioterapia adyuvante. El abordaje abierto se usó en 17 pacientes (89,5%), mientras que a 2 pacientes (10,5%) se les realizó una técnica laparoscópica. Complicaciones postquirúrgicas ocurrieron en 8 pacientes (42,1%), de las cuales ninguna fue de grado IV o V. La mediana de seguimiento fue de 66 meses (rango 3-312). La mayoría de los pacientes (n=15, 78,9%) permanecieron libres de enfermedad únicamente con un manejo quirúrgico. Ninguno recibió terapia adyuvante con mitotane. Cuatro pacientes (21%) presentaron metástasis metacrónicas y 3 (15,8%) recurrencia local tras una mediana de tiempo de 10,5 meses (rango 2-60) y 9,3 meses (rango1,5-30), respectivamente. La tasa de supervivencia globala los 5 años fue del 47,4%. CONCLUSIONES: Nuestros resultados confirman tanto la naturaleza impredecible del carcinoma adrenocortical como la aceptación del rol primario de la cirugía en su manejo. El uso de un agente adyuvante fue menos frecuente en esta serie respecto a lo respaldado actualmente. Sin embargo, un manejo multidisciplinar debería ser el primer paso a seguir en el tratamiento de esta rara enfermedad.

Outcomes following surgical management of adrenocortical carcinoma: a single-center experience / Resultados después del manejo quirúrgico del carcinoma adrenocortical: una experiencia de un solo centro

Objetive: Adrenocortical carcinoma(ACC) is a rare and heterogeneous disease, with challenging management and poor prognosis. Surgery withcurative intent is the preferred treatment option for localized disease, with a reported 5-year survival rate of55% for complete resections. However, owing to thehigh risk of recurrence there is a need for adjuvant therapies, such as mitotane, an adrenolytic drug, or irradiation, while in advanced disease the standard of careis a combined chemotherapy scheme. The aim of thisstudy was to report our experience in the surgical management and outcomes of ACC patients. Material and methods: A retrospective observational study was performed in a cohort of ACC patientswho had undergone surgical resection (open or laparoscopic approach) and were followed up at our tertiary hospital. Patients with localized or locally advanced disease were included in the analysis. All medical records,including clinical, surgical, pathologic, and follow-updata, were collected and analyzed. Results: A total of 19 ACC patients were managedat our center between August 1990 and August 2013.The median age at diagnosis was 50.5 years (range19–72), and most patients were males. Abdominalpain was the most common clinical presentation (n=9,47.4%). Abdominal contrast-enhanced computed tomography (CT) was performed in all cases. Only 3 tu-mors (15.8%) were functional and most were stage II atdiagnosis (n=9, 47.4%). No patient presented metastasis. Of the 19 patients, 18 (94.7%) underwent surgerywith curative intent, while one (5.3%) received adjuvantradiotherapy (ART). The open approach was used in17 patients (89.5%), while the remaining 2 (10.5%)underwent laparoscopy. Postoperative complicationsoccurred in 8 patients (42.1%); none were of grade IVor V. Median follow-up was 66 months (range 3–312).The majority of patients (n=15, 78.9%) were diseasefree with surgery alone. None received adjuvant mitotane therapy...(AU)

Objetivo: El carcinoma adrenocorticales una enfermedad heterogénea y rara que conllevaun manejo complicado y cuyo pronóstico es malo. Anteuna enefermedad localizada el manejo quirúrgico es deelección, observando una tasa de supervivencia a los 5años del 55% en resecciones completas. Sin embargo,debido a la alta tasa de recurrencias, se requiere complementar el manejo con una terapia adyuvante comoes el caso del mitotane, un agente adrenolítico, o laradioterapia. En casos de enfermedad avanzada la terapia de elección incluye una pauta de quimioterapiacombinada. El objetivo del presente estudio es reportarnuestra experiencia en el manejo quirúrgico y resultadosobtenidos de los pacientes con diagnóstico de carcinoma adrenocortical. Materiales y métodos: Se realizó un estudio observacional de una cohorte de pacientes diagnosticados de carconinoma adrenocortical que requirieronun manejo quirúrgico (abierto o laparoscópico) y querealizaron su seguimiento en nuestro hospital terciario.Se incluyó a pacientes con enfermedad localizada ylocalmente avanzada en el análisis. Todos los dados clínicos, quirúrgicos, patológicos y de seguimiento fueronrecolectados para el análisis. Resultados: Entre agosto del 1990 y agosto del2013 un total de 19 pacientes diagnosticados decarcinoma adrenocortical fueron tratados en nuestrocentro. La mediana de edad al diagnóstico fue 50,5años (rango 19-72), siendo la mayoría hombres. Elsíntoma inicial mas frecuente fue el dolor abdominal(n=9, 47,4%). Una tomografía computarizada con contraste fue realizada en todos los casos. Sólo 3 tumores(15,8%) eran funcionales y la mayoría correspondíaa un estadio II al diagnóstico (n=9, 47,4%). Ningúnpaciente presentaba metástasis. De los 19 pacientes,18 (94,7%) requirieron cirugía con intención curativa,mientras que a uno (5,3%) se le realizó radioterapiaadyuvante...(AU)

Carcinoma adrenal em crianças: estudo longitudinal em minas gerais, brasil / Adrenal carcinoma in children: longitudinal study in minas gerais, brazil

RESUMO Objetivo: Analisar as características clínicas, laboratoriais e histopatológicas e o percurso até o estabelecimento do diagnóstico e do tratamento de pacientes com carcinoma de suprarrenal (CSR). Métodos: Estudo retrospectivo com 13 pacientes tratados no serviço de oncologia pediátrica do Hospital das Clínicas da Universidade Federal de Minas Gerais (HC-UFMG) entre 2004 e 2015. Resultados: A idade ao diagnóstico variou de 1,0 a 14,8 anos (mediana: 2,0 anos). As manifestações de hipercortisolismo foram identificadas em todos os casos, e as de virilização, em todas as meninas. Todos os pacientes preencheram os critérios de Weiss para diagnóstico histopatológico de CSR. A imuno-histoquímica foi realizada em 61,5% dos casos. A maioria dos pacientes apresentou doença em estádio I (76,9%). Todos foram submetidos à ressecção tumoral total. Dois pacientes (estádios III e IV) receberam quimioterapia associada ao mitotano. O único óbito observado foi do paciente com doença em estádio IV. A probabilidade de sobrevida global para todo o grupo aos 5,0 anos foi de 92,3±7,4%. A mediana de tempo entre o início dos sintomas e o diagnóstico foi de 9,5 meses, e de 6,0 meses entre a primeira consulta e o início do tratamento. Conclusões: A baixa idade ao diagnóstico, o predomínio de casos com doença localizada e a ressecção tumoral completa - com apenas um caso de ruptura de cápsula tumoral - são possivelmente a explicação para a evolução favorável da população estudada. O longo percurso entre o início dos sintomas e o diagnóstico sugere a importância da capacitação dos pediatras para o reconhecimento precoce dos sinais e dos sintomas do CSR.

ABSTRACT Objective: To analyze clinical, laboratory and histopathological features and the path to diagnosis establishment and treatment of patients with adrenal carcinoma (AC). Methods: Retrospective study with 13 patients assisted at the pediatric oncology service of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, between 2004 and 2015. Results: Age at diagnosis ranged from 1.0 to 14.8 years (median: 2.0 years). Manifestations of hypercortisolism were identified in all cases and virilization in all girls. All patients met the Weiss criteria to AC histopathological diagnosis. Immunohistochemistry was performed in 61.5% of the cases. Most patients had stage I disease (76.9%). All subjects were submitted to total tumor resection. Two patients (stages III and IV disease) received chemotherapy associated to mitotane. The only death case was that of a patient with stage IV disease. The probability of overall survival for the entire group up to 5.0 years was 92.3±7.4%. The median time between the onset of symptoms and diagnosis was 9.5 months, and 6.0 months between first visit and start of treatment. Conclusions: Low age at diagnosis, predominance of cases with localized disease and complete tumor resection - with only one case of tumor capsule rupture - can possibly explain the favorable evolution of the studied population. The long period between onset of symptoms and diagnosis highlights the importance of training pediatricians for early recognition of AC signs and symptoms.

Carcinoma adrenocortical oncocítico virilizante / Adrenal oncocytic virilizing carcinoma

Las neoplasias oncocíticas se encuentran raramente en la glándula suprarrenal. Suelen ser benignos y no funcionales. Existen informes extremadamente limitados de neoplasias oncocíticas suprarrenales. Alrededor del 20% de las neoplasias oncocíticas adrenocorticales muestran componentes malignos y el 10-20% produce hormonas que pueden causar desbalances hormonales. Se presenta un carcinoma adrenocortical oncocítico virilizante en mujer de 35 años de edad quien acudió a consulta por presentar hipomenorrea secundaria de seis meses de duración acompañada de hirsutismo y agravamiento del acné que afectaba principalmente la cara. El examen de laboratorio revela niveles elevados de testosterona libre. La tomografía computada mostró tumor multinodular en la glándula suprarrenal derecha con necrosis central y sin evidencia de linfadenopatía o invasión de estructuras que la rodeaban. Se programó la adrenalectomía derecha lográndose resección completa del tumor. Después de la cirugía, se normalizaron los ciclos menstruales, el hirsutismo, el acné y el resto de las pruebas. El examen histopatológico del tumor fue compatible con carcinoma adrenocortical oncocítico(AU)

Oncocytic neoplasms are found more rarely in the adrenal gland. They are usually benign and nonfunctional. There are limited reports of adrenal oncocytic neoplasms. About 20% of adrenocortical oncocytic neoplasms show malignant components and 10-20% produce hormones that can cause hormonal imbalances. We present a virilizing oncocytic adrenocortical carcinoma in a 35-year-old woman who consulted for hypomenorrhea accompanied by hirsutism and face acne worsening. Laboratory test revealed high levels of free testosterone. Computed tomography showed multinodular tumor of the right adrenal gland with central necrosis and without evidence of lymphadenopathy or invasion of surrounding structures. A right adrenalectomy was performed. After surgery, menstrual cycle, hirsutism and acne, as well as hormonal tests were normal. Histopathological examination of tumor showed an oncocytic adrenocortical carcinoma(AU)

Tumores e hiperplasias adrenocorticais: identificação de possíveisdoenças hereditárias / Recognition of hereditary diseases related to adrenocortical tumors andhyperplasias

A alta prevalência de tumores da glândula adrenal deve-se, em parte, ao avanço dos métodos de imagem. Os adenomas, carcinomas e hiperplasias oriundos do córtex adrenal são responsáveis por 80 a 90% dos processos tumorais. Alguns casos são herdados e podem estar associados a efeito compressivo de massa tumoral, hipersecreção de esteroides ou manifestações clínicas em outros órgãos. Considerando as hiperplasias e tumores adrenocorticais, o objetivo desse trabalho foi auxiliar os médicos na identificação de pacientes que apresentem risco para doença hereditária. As neoplasias e hiperplasias adrenocorticais podem ser encontradas em síndromes hereditárias, como a síndrome de Li-Fraumeni, síndrome de Beckwith-Wiedemann, neoplasia endócrina múltipla do tipo I, síndrome de Gardner e no complexo de Carney. A hereditariedade também está associada com doenças adrenocorticais na hiperplasia adrenal congênita, no aldosteronismo primário e/ou na síndrome de Cushing (doença clínica ou subclínica) na hiperplasia adrenal macronodular primária. Essa revisão descreve as características clínicas e os defeitos genéticos responsáveis pelas síndromes hereditárias. Relacionamos também a classificação histopatológica dos processos expansivos com os principais sinais clínicos e os genes relacionados. A identificação de defeitos genéticos em células germinativas nessas doenças familiais permite o conhecimento de alterações somáticas em alguns tipos de processos tumorais adrenocorticais de etiologia esporádica. Considerando a prevalência dos tumores do córtex adrenal, a identificação de predisposição hereditária é essencial para assegurar a conduta clínica correta do paciente e o aconselhamento genético de seus familiares.

The adrenal gland tumors are prevalent due in part by the widespread use of imaging studies. Adenomas, carcinomas and hyperplasias, originating from the adrenal cortex, account for 80-90% of adrenal tumoral processes. Some cases are inherited and may be associated with local mass effect, steroid hypersecretion and/or clinical manifestation in other organs. In the context of adrenocortical tumors and hyperplasias, the purpose of this article is to assist physicians in identifying patients who may be at risk of hereditary diseases. Adrenocortical hyperplasias and neoplasias can be found in familial tumor syndromes, such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia type 1, Gardner syndrome and Carney complex. Heredity has been also associated with adrenocortical lesions in congenital adrenal hyperplasia, primary aldosteronism and/or Cushing syndrome (overt or subclinical disease) in primary macronodular adrenal hyperplasia (PMAH). This review describes the clinical recognition and genetic defects that have been found to be responsible for these hereditary diseases. Furthermore, we present the histopathologic classification of adrenocortical expansive processes in correlation to the main clinical features and related genes. The identification of germline genetic defects in such familial diseases lead to the identification of somatic alterations in a subgroup of sporadic adrenocortical lesions. Considering the prevalence of adrenocortical tumors, identification of a hereditary predisposition is essential to assure the adequate clinical management of the patient and to offer the genetic counselling to family members.

Análise comparativa dos transcritomas do córtex adrenal normal e adenocarcinoma do córtex adrenal / Comparative analysis of normal adrenal cortice and adrenocortical carcinoma transcriptomes

A carcinogênese do córtex da supra-renal é um processo complexo que envolve alterações genéticas múltiplas e sequenciais. Embora algumas dessas alterações já tenham sido caracterizadas, de modo geral estes mecanismos permanecem pouco compreendidos. Um conhecimento mais aprofundado dos mesmos não só levaria à descoberta de novos marcadores de prognóstico como também a alvos terapêuticos em potencial. A fim de melhor caracterizarmos os mecanismos envolvidos na progressão maligna do tumor e selecionarmos genes candidatos a serem marcadores de malignidade e alvos terapêuticos, nós estudamos os RNAs de uma linhagem celular derivada de um tumor adrenocortical maligno (NCI-H295A) e um espécime de tumor do córtex da supra-renal por "Differential Display" (DDRT-PCR). Foi selecionado um total de 317 transcritos únicos diferencialmente expressos, com base na análise densitométrica digital dos géis de DDRTPCR. A anotação funcional dos genes hiper-expressos mostrou relação com motilidade celular e proliferação. Entre os hipo-expressos foram identificados genes envolvidos na regulação de transcrição, síntese e processamento de RNA e remodelamento da cromatina. A expressão de dois genes entre os transcritos selecionados foi verificada por RT-PCR semi-quantitativa em 19 tumores adrenocorticais adultos e pediátricos, metastáticos e não metastáticos. Os genes da fucosiltransferase-11 e do supressor tumoral BCSC-1 (hiper- e hipo-regulado, respectivamente) encontraram-se diferencialmente expressos nos subgrupos específicos das 19 amostras tumorais. Em suma, o DDRT-PCR revelou-se uma ferramenta valiosa para uma análise global dos transcritomas do córtex da supra-renal e para selecionar genes com possível envolvimento na tumorigênese adrenocortical. Novos aspectos da biologia, progressão e possíveis alvos terapêuticos moleculares puderam ser vislumbrados.

There are important gaps in the present knowledge about adrenocortical tumorigenesis. For this reason we compared by Differential Display RNAs from a carcinoma-derived cell line (NCI-H295A) and a metastatic adrenocortical tumor and characterized 317 differentially expressed transcripts. The up-regulated genes are mainly related to cell motility and proliferation. Among the down-regulated genes, those involved in regulation of transcription, RNA synthesis and processing and chromatin remodeling were identified. Differential expression of FUTT11 and BCSC-1 tumor suppressor gene were confirmed in specific subsets of 19 adult and pediatric adrenocortical tumors and might serve as marker for malignancy. Our data revealed previously unknown aspects of adrenal tumorigenesis.

Tumores adrenocorticales: a propósito de dos casos / Adrenocortical tumors: Report of two cases

Los tumores adrenocorticales son poco frecuentes en la población infantil. En esta comunicación se describen dos pacientes atendidos en el Servicio de Cirugía Pediátrica del Hospital Universitario Japonés, de la ciudad de Santa Cruz de la Sierra, Bolivia, presentando precozmente vello pubiano. La tomografía abdominal contrastada, reveló en ambos casos, tumor adrenocortical y el tratamiento efectuado fue la extirpación de la masa tumoral. Se confirmó el diagnóstico por Anatomía patológica concluyendo tratarse de un carcinoma adrenocortical y de otro adenoma adrenocortical.

The adrenocortical tumors are not very frequent in the infantile population. We describe two cases attended in the ward of Pediatric Surgery of the Hospital Universitario Japonés, at Santa Cruz de la Sierra, Bolivia. The patients, a three years-old girl and a four years-old boy had a precocious pubic body hair. The CT revealed in both cases adrenocortical tumors, and they were treated with the extirpation of the tumoral mass. Their diagnosis were confirmed by pathological reports: an adrenocortical carcinoma in the girl and an adrenocortical adenoma in the boy.