Metastatic Paraganglioma

Abstract

Paragangliomas (PGLs) are rare chromaffin cell tumors that can often be cured by resection. Although described for the first time in 1886 1 , the diagnosis of PGL remains a challenge, because patients do not present with characteristic signs and symptoms. If untreated, PGL can have a devastating outcome due to myocardial infarction, severe hypertension, stroke and/or arrhytmia caused by catecholamine excess. Even after proper diagnosis, the risk of metastatic disease remains. In recent years the opinion that metastatic disease is rare in PGL had to be revised, particularly in patients presenting with extra-adrenal PGL, with a PGL exceeding a size of 5 cm and/or carrying an SDHB germline mutation (especially for children and adolescents). In up to 10 % of patients, metastases are already present at diagnosis of PGL.Measurement of plasma and urinary metanephrine levels has long been used effectively in the diagnosis of PGL. Recently, a dopaminergic phenotype (excess dopamine, L-3,4-dihydroxyphenylalanine and or methoxytyramine) was recognized as a good indicator for metastatic disease. Vast progress in targeted PET imaging (e.g. 18 F-FDA, 18 F-FDOPA, 18 F-FDG) now allows for reliable early detection of metastatic disease. However, once metastatses are present, treatment options are limited. Survival of patients with metastatic PGL is variable. Depending on the study population the overall 5 year survival is 35-60 %, 2 .Here we review recent advances involving findings about the genetic background, the molecular pathogenesis, new diagnostic indicators, pathologic markers and emerging treatment options for metastatic PGL. DefinitionFollowing the definition of the world health organization, paragangliomas (PGLs) are chromaffin cell tumors developing from the sympathetic and parasympathetic ganglia throughout the abdomen and head and neck area. A PGL arising from the adrenal gland is called pheochromocytoma (PHEO). In addition, here we will distinguish between Corresponding author: Karel Pacak, M.D., Ph.D., D.Sc., Chief, Section on Medical Neuroendocrinology, Professor of Medicine, Reproductive and Adult Endocrinology Program, NICHD, NIH, Building 10, CRC, 1-East, Room 1-3140, 10 Center Drive, MSC-1109, Bethesda, Maryland 20892-1109. DISCLOSURE STATEMENT: The authors have nothing to disclose. 1 Carbidopa has been shown to increase the tumor-to-background ratio of 18 F-FDOPA uptake in PGL, particularly PHEO 68Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Rule of 10 % OvercomePGL has long been considered as the disease of 10 % (10 % metastatic, 10 % f...

DIAGNOSIS OF ENDOCRINE DISEASE: Biochemical diagnosis of phaeochromocytoma and paraganglioma

“…However, still many patients remain undetected, therefore the prevalence of PPGL in autopsy studies is 0.05% (2). Most tumours are benign but w10-15% are defined as malignant based on the development of metastases in nonchromaffin tissues such as lymph nodes, liver and bone (4).…”

Sporadic paraganglioma caused by de novo SDHB mutations in a 6-year-old girl

“…Approximately 40 % of SDHB mutation carriers will develop metastases, and the rate seems to be higher in pediatric patients (47-85 %) [5,6,15]. Genetic screening tests should therefore be considered for asymptomatic children in families with a SDHB mutation carrier as well as for children who presented with PCC/PGL.…”

“…In the majority of pediatric patients (up to 80 %), tumors are related to germline mutations in at least one of these susceptibility genes [6,13,14,19].…”

Toward tailored medicine (and beyond): the phaeochromocytoma and paraganglioma model

“…They can occur as sporadic cases, but up to 30 % of patients with PGL have a family history. In 10 % of patients with PCC the tumour is associated with multiple endocrine neoplasia syndrome 2A or 2B, von Hippel-Lindau disease or neurofibromatosis type I. Familial PGL associated with mutations in succinate dehydrogenase complex subunit B (SDHB) shows a high rate of malignancy and hypersecretion of normetanephrine and norepinephrine [2]. Conversely, PGL associated with mutations in succinate dehydrogenase complex subunit D (SDHD) or C (SDHC) is almost always benign, and is typically located in the head and neck region.…”