Surgical Management of the Succinate Dehydrogenase–Associated Familial Paraganglioma Syndromes

Paragangliomas (PGLs) are rare neuroendocrine tumors arising from the neural crest cells in the extra-adrenal location. Paragangliomas can be sporadic or associated with the other hereditary tumor syndromes.¹

In this article, we report on 2 cases of the succinate dehydrogenase (SDH)–associated familiar PGL syndrome and review available literature on etiologic course, diagnosis, and management of this condition.

A 39-year old man with familial history of PGL developed arterial hypertension and subsequent myocardial infarction, requiring placement of coronary stents. Genetic screening was performed because of familial history, with results being positive for an SDHB gene mutation. A computed tomographic (CT) scan of the abdomen reflected a 1.5-cm para-aortic mass (Figure 1). The patient was also found to have elevated catecholamine metabolite levels in his urine. Exploratory laparotomy was performed and a 2-cm para-aortic mass was excised with clear margins. Pathologic results showed a well-encapsulated tumor with argyrophilic tumor cells positive on immunochemical analysis for chromogranin and negative for S-100 protein, consistent with the diagnosis of PGL. The patient had complete resolution of the arterial hypertension with normalization of urinary metanephrine levels postoperatively. No evidence of recurrent disease was noted during the 3-year follow-up period.

A 47-year old woman, the sister of patient 1, was found to have elevated blood pressure. Because of family history, genetic screening and laboratory tests were performed. The patient was found to be a carrier of the SDHB gene mutation and also had an elevated 24-hour urinary catecholamine metabolite level. An abdominal CT scan showed a mass in a retrocaval position (Figure 2) with focal metaiodobenzylguanidine scan uptake. During laparotomy, an approximately 5-cm encapsulated mass was excised en bloc with the right adrenal gland with clear margins. Pathologic results of the specimen reflected a sharply circumscribed tumor, with the tumor cells organized in cell balls positive for chromogranin and synaptophysin and negative for S-100 protein, consistent with PGL. Her urinary catecholamine metabolite level was normal after surgery and her arterial hypertension had resolved. No tumor recurrence was detected 2 years after resection.

Review of the literature was performed using PubMed article searches for the terms familialparaganglioma and extra -adrenalparaganglioma. Articles pertinent to the topic were retrieved in full-text form and relevant information is presented in the “Comment” section.

Paragangliomas have an estimated annual incidence of 2 to 8 cases per million of the general population per year.² Recent evidence suggests that as much as 30% of all patients with PGL have an inherited condition.^{1 ,3} The associated syndromes include neurofibromatosis type 1 syndrome, von Hippel-Lindau disease, multiple endocrine neoplasia type 2 syndrome, PGL syndromes type 1 (PGL-1) through type 4 (PGL-4), and Carney triad.³ Not all PGLs are catecholamine secreting and thus are divided into functional (sympathetic) and nonfunctional (parasympathetic) types. They can be found intra-abdominally and in the thorax or neck/head areas.³

In recent years, SDH -associated PGL syndromes have become better characterized.^{3 - 5} Mutations of the genes and encoding of different subunits of the mitochondrial SDH enzyme have led to the development of different forms of PGL syndrome: (1) the SDHD gene (11q23) in PGL-1, (2) the SDH5 /SDHAF2 gene (11q13.1) in PGL-2, (3) the SDHC gene (1q21) in PGL-3, and (4) the SDHB gene (1p36.1-p35) in PGL-4.^{3 - 4 ,6} The percentage of the de novo mutations is unknown, and the transmission appears to be in an autosomal-dominant fashion.⁶ The PGL syndrome type determines the clinical phenotype. For example, PGL-1 through PGL-3 predominantly result in the development of parasympathetic (nonfunctioning) PGLs in the head/neck region, which have rare malignant potential and 86% to 100% penetrance by age 50 years.^{4 ,6} Conversely, PGL-4 is predominantly associated with the abdominal functioning (sympathetic) and extra-adrenal PGLs with a high malignant potential (up to 50%) and about 80% penetrance by age 50 years.^{4 ,6}

Patients with functional PGLs usually present with symptoms of catecholamine hypersecretion.⁶ Nonfunctioning (parasympathetic) PGLs are located most frequently in the head/neck region and manifest by producing mass effect.

Biochemical tests and localization studies are used to diagnose PGLs. In adult patients, sensitivity and specificity of the plasma normetanephrine/metanephrine level are 98% and 92%, respectively.⁷ When abnormal, findings from a 24-hour urinary test for normetanephrines/metanephrines result in 97% sensitivity and 69% specificity.⁸ In nonmetastatic PGLs, the first choice of imaging is CT/magnetic resonance imaging with 100% sensitivity for tumor localization.⁹ In the case of metastatic PGLs, positron emission tomography with fluorodeoxyglucose F 18/computed tomography has 74% sensitivity, followed by iodine 123–labeled metaiodobenzylguanidine scans with 57% sensitivity and CT/magnetic resonance imaging offering only 45% sensitivity.⁹ Factors that can decrease ¹²³I-metaiodobenzylguanidine scan sensitivity include familial PGL syndromes, malignant disease, and the extra-adrenal location.

Once the diagnosis is established, surgical resection of all symptomatic tumors is necessary. Paragangliomas are usually well defined and do not infiltrate surrounding tissues, making surgical resection with clear margins relatively easy to achieve. No specific resection margins are necessary unless invasion into surrounding tissue/organs is demonstrated intraoperatively. Nonfunctioning PGLs causing minimal or no symptoms can be safely observed. Appropriate adrenergic blockade is an essential part of presurgical preparation.⁵ The surgical approach can be open or minimally invasive. A large series from specialized institutions confirmed the effectiveness and safety of the minimally invasive surgical approach.¹⁰ Malignancy is diagnosed by the presence of the distant metastases. Factors associated with malignancy include young age, size greater than 5 cm, dopamine hypersecretion, and SDHB gene mutation (PGL-4).^{2 ,5} According to the Mayo Clinic experience with patients with PGL, a cure was obtained in 69% of patients with 59% to 100% survival at 20 years in metastatic vs nonmetastatic disease.² A recurrence rate of 21% at 5 years has been reported, indicating the need for lifelong surveillance.¹¹

A family history of PGL or pheohromocytoma, previous head and neck PGLs, multiple tumors, or young age at the time of diagnosis should prompt genetic testing for SDH gene mutations.⁸ Current recommendations for screening suggest genetic testing by age 10 years or at least 10 years before the earliest age at diagnosis for all first-degree relatives of a patient with SDHD, SDHC, or SDHB gene mutations.^{2 ,6}

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