An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma.

Paragangliomas and pheochromocytomas (PPGL) are rare neuroendocrine tumours characterized by a strong genetic determinism. Over the past 20 years, evolution of PPGL genetics has revealed that around 40% of PPGL are genetically determined, secondary to a germline mutation in one of more than twenty susceptibility genes reported so far. More than half of the mutations occur in one of the SDHx genes (SDHA, SDHB, SDHC, SDHD, SDHAF2), which encode the different subunits and assembly protein of a mitochondrial enzyme, succinate dehydrogenase. These susceptibility genes predispose to early forms (VHL, RET, SDHD, EPAS1, DLST), syndromic (RET, VHL, EPAS1, NF1, FH), multiple (SDHD, TMEM127, MAX, DLST, MDH2, GOT2) or malignant (SDHB, FH, SLC25A11) PPGL. The discovery of a germline mutation in one of these genes changes the patient's follow-up and allows genetic screening of affected families and the presymptomatic follow-up of relatives carrying a mutation.

15 YEARS OF PARAGANGLIOMA: Pheochromocytoma, paraganglioma and genetic syndromes: a historical perspective.

The last decades have elucidated the genetic basis of pheochromocytoma (PC) and paraganglioma (PGL) (PCPGL)-associated hereditary syndromes. However, the history of these syndromes dates back at least another 150 years. Detailed descriptions by clinicians and pathologists in the 19th and 20th centuries led to the recognition of the PCPGL-associated syndromes von Hippel-Lindau disease, neurofibromatosis type 1, and multiple endocrine neoplasia type 2. In the beginning of the current millennium the molecular basis of the hereditary PGL syndrome was elucidated by the discovery of mutations in genes encoding enzymes of the Krebs cycle, such as succinate dehydrogenase genes (SDHx) and other mutations, causing 'pseudo-hypoxia' signaling. These recent developments also marked a paradigm shift. It reversed the traditional order of genetic research that historically aimed to define the genetic basis of a known hereditary syndrome but now is challenged with defining the full clinical phenotype associated with a newly defined genetic basis. This challenge underscores the importance to learn from medical history, continue providing support for clinical research, and train physicians with regards to their skills to identify patients with PCPGL-associated syndromes to extend our knowledge of the associated phenotype. This historical overview provides details on the history of the paraganglial system and PCPGL-associated syndromes. As such, it hopefully will not only be an interesting reading for the physician with a historical interest but also emphasize the necessity of ongoing astute individual clinical observations and clinical registries to increase our knowledge regarding the full phenotypic spectrum of these conditions.

[History and epidemiology]. / Recuerdo histórico y epidemiología.

The development of knowledge of paragangliomas has been inextricably linked to the development of all fields of medicine. Throughout history, both knowledge of diseases and technical improvements in diagnosis have served to understand these tumors, although unanswered questions remain. From the XVIII century to the XXI century events sometimes unexpected and other times intensely sought have occurred that have helped to identify the characteristics of these tumors. These events have ranged from description of paragangliomas to their genetic diagnosis. The incidence of paragangliomas is not high. Nevertheless, the variability of these tumors in terms of their localization, forms of presentation, possibilities of metastasis or their hereditary component has been well characterized.

Recuerdo histórico y epidemiología / History and epidemiology

El desarrollo del conocimiento de los paragangliomas ha ido inexorablemente unido al desarrollo de la medicina en todos sus campos. Tanto el propio conocimiento de las enfermedades como la mejora técnica en el diagnóstico han servido, a lo largo de la historia, para llegar a entender esta patología, que presenta, por otra parte, interrogantes sin resolver. Desde el siglo XVIII hasta el siglo XXI se han ido sucediendo acontecimientos, a veces ocasionales y a veces profundamente buscados, que han ido revelando cómo es esta patología, desde la descripción de la enfermedad hasta el diagnóstico genético. Su incidencia no es elevada pero, a pesar de ello, su variabilidad en cuanto a localización, formas de presentación, posibilidad de metastatizar o su componente hereditario está perfectamente estudiada (AU)

The development of knowledge of paragangliomas has been inextricably linked to the development of all fields of medicine. Throughout history, both knowledge of diseases and technical improvements in diagnosis have served to understand these tumors, although unanswered questions remain. From the XVIII century to the XXI century events–sometimes unexpected and other times intensely sought–have occurred that have helped to identify the characteristics of these tumors. These events have ranged from description of paragangliomas to their genetic diagnosis. The incidence of paragangliomas is not high. Nevertheless, the variability of these tumors in terms of their localization, forms of presentation, possibilities of metastasis or their hereditary component has been well characterized (AU)

Organs of Zuckerkandl: their surgical significance and a review of a century of literature.

BACKGROUND: Organs of Zuckerkandl (O of Z) harbor the potential for deadly paragangliomas. Paragangliomas are one of the surgical causes of hypertension. Major treatises of medicine offer very little information on this topic. METHODS: PubMed Medline and Google searches were performed to obtain reported cases of paragangliomas of the O of Z. A total of 135 cases of paragangliomas of the O of Z were found. Each case was reviewed and charted. Charts then were analyzed. RESULTS: Seventy-four percent of patients with this neoplasm have hypertension. Eighty percent of patients undergo an operation with more than 30% having an incorrect preoperative diagnosis. These tumors have a 43% mortality when presenting acutely. CONCLUSIONS: Individuals aged < or =50 years with hypertension should be considered for screening for pheochromocytoma/paraganglioma with uring and/or serum catecholamines. Twenty-four-hour collections for urinary metanephrines and vanillylmandelic acid are diagnostic of functional tumors. A high degree of suspicion should follow with radiologic and chemical diagnostic studies. Triple-phase helical computed tomographic scans, metaiodobenzyl-guanidine scans, and magnetic resonance imaging with gadolinium-diethylenetriaminepentaacetic acid infusion are the standard for radiologic diagnosis. Treatment is always surgical excision. Phase II trials are in order for neoadjuvant and adjuvant treatment options.

Paraganglioma retroperitoneal extra adrenal maligno simulando tumor renal / Malignant extra-adrenal retroperitoneal paraganglioma

The modern concept of some embryological structures found as dispersed cells at the retroperitoneal region, is to be considered as a great group of structures with similar embryological origin that can be divided in various anatomical and functional group. A case of a malignant extra-adrenal retroperitoneal paraganglioma is described in a 14 year-old man who presented an episode of hematuria following a history of trauma. A computed tomography was performed and showed a solid mass in lower pole of the left kidney. A magnetic resonance imaging examination was later indicated. Because of the persistence of the mass, a surgical exploration was performed and the tumor was removed. The pathological examination demonstrated a malignant paraganglioma. These tumors are rare and difficult to diagnose pre-operatively. The prognosis is poor and the best results reported are around 3 years survival

Paraganglioma extra-adrenal / Extra-adrenal paraganglioma

Os paragangliomas extra-adrenais constituem um grupo raro de doenças, porém assumem dimensäo maior quando analisados em suas múltiplas facetas de apresentaçäo clínica. A trajetória histórica destes tumores, revela num passado näo täo longínquo, as dificuldades para o reconhecimento e correto diagnóstico dos mesmos. E, principalmente, o temor da abordagem cirúrgica, decorrente do alto grau de complicaçöes operatórias imediatas e tardias. A experiência na conduta e terapêutica de vinte casos destes tumores em um periodo de 35 anos é revista e analisada, objetivando comparar os dados do Departamento de Cirurgia de Cabeça e Pesco13o do Hospital A. C. Camargo da Fundaçäo Antonio Prudente com os obtidos e relatados pela literatura mundial.