Paragangliomas (PGL) are neuroendocrine neoplasms deriving from paraganglia, specialized neural crest-derived groups of chromaffine cells able to synthesize and secrete various amines.
Parasympathetic paraganglia are localized almost exclusively in head and neck region along the branches of the cranial nerves, acting as chemoreceptors [1]. The sympathetic paraganglia are symmetrically distributed along the paravertebral axis from the superior cervical ganglion to the pelvis and predominantly located in the abdomen where the largest ones are the adrenal medullas.
Because of the widespread distribution of paraganglia, PGL can occur at virtually all locations in the body except the brain and bone. Parasympathetic-derived PGL arise from parasympathetic ganglia located along the cranial nerves in the neck and at the base of the skull (head and neck paraganglioma, HNPGL); sympathetic-derived PGL arise from adrenal medulla (pheochromocytoma, PHEO) or extra-adrenal sympathetic ganglia of thorax, abdomen, and pelvis (Table 1) (Fig. 1, Fig. 2) [2].
Usually, sympathetic PGL tend to be functional and symptomatic, while HNPGL are non-functional and may present with mass effect [1], [2], ∗[3].
About 40% of PGL are caused by specific germline mutations and are hereditary, even if penetrance and clinical expressivity may be incomplete. In this setting PGL may be also associated to other tumors (syndromic PGL) [3]. During the last two decades more than 20 germline mutations causing PHEO/PGL have been identified; they can be grouped into two major clusters: mutations involved with the pseudo-hypoxic pathway and reduced oxidative response (including VHL, EGLN1, SDH, IDH, HIF2A, and FH genes), and mutations associated with abnormal activation of kinase signaling pathways (RET, NF1, KIF1Bbeta, MAX and TMEM127 gene mutations) [4]. The phenotype of syndromic PHEO/PGL, including secretotype, age at onset, tumor aggressiveness, clinical presentation and associated diseases/neoplasia, is influenced by genotype as well as anatomic site of origin (Table 2). Thus, all individuals with PHEO/PGL should be referred for clinical genetic testing. Hereditary PHEO/PGL should be suspected in any individual with a PGL or PHEO, particularly those with family history of PHEO/PGL or sudden unexplained death of cardiovascular origin, or with multiple, bilateral, early onset (<45 years), extra-adrenal and metastatic disease. In fact, compared to sporadic variants, syndromic and hereditary PGL may occur at earlier age; they may occur at multiple sites (even if asynchronously), and as a malignant or recurrent disease (Fig. 3). However, familial history may be absent because of variable penetrance of putative genes and the phenomenon of parental imprinting (as in case of SDHD mutations), simulating an apparently sporadic variant [5].
PGL are usually benign tumors, but malignancy varies between 10 and 40%; formally it cannot be predicted only by histology but should be definitively confirmed in presence of regional lymph-nodal or distant metastases to non-endocrine tissue. However, rapidly enlarging painful mass, younger onset age and specific genetic background (SDHB, FH and MDH2 mutations) are risk factors for malignancy [6] (Table 2).
Surgery represents the only curative treatment in hereditary PGL but it should be tailored according to the age of patient, genotype, hormonal secretion, biologic behaviors/aggressiveness, number and location of PGL, and the presence of associated tumors, as occur in MEN2, VHL and SDHx-related PGL [7]. The timing, the extent and the approach of surgery (minimally invasive or open) should take into account the variable behaviors of these tumors, the multiple locations (neck, thorax, abdomen) in the same patient, and the tendency to recur metachronously (with variable disease-free interval) and the surgical morbidity. Thus, alternative strategy to surgery and a prolonged, long-life follow-up may be required in patients with hereditary PGL.
The aim of this paper is to develop a surgical concept for the most frequent hereditary PGL based on type of mutation, risk of malignancy, and risk factors for potential surgical complications.
HNPGL are neural crest-derived neuroendocrine neoplasms arising from parasympathetic head and neck paraganglia along the branches of the glossopharyngeal and vagus nerves, and account for 7–16% of all chromaffine tumors [8], [9].
Although most HNPGL are sporadic, nearly 40% presenting with a single mass and 90% with multifocal and/or bilateral disease are hereditary. Hereditary HNPGL are most frequently associated with PGL syndromes due to germline mutations in SDH subunits (Table 2): SDHD
Sympathetic PGL may arise from the adrenal medulla (PHEO, 80–85%) or from extra-adrenal ganglia of the sympathetic chain in thorax, abdomen, and pelvis (15%–20%). In more than one third of patients they are linked to germline mutations ∗[3], ∗[6]. The rarity of PGL calls for a multidisciplinary approach to each patient involving endocrinologists, surgeons, medical oncologists, and genetic counselors to optimize patient outcome. Hereditary thoraco-abdominal PGL are predominantly related to
Most of hereditary sympathetic PGL hypersecrete catecholamines, causing secondary hypertension or typically a paroxysmal hypertension accompanied by an abrupt onset of headaches, palpitations, diaphoresis, anxiety and chest pain. However, these tumors can mimic a variety of conditions, earning the title of “great mimic”. Actually, about 30% of patients with sympathetic PGL are either normotensive or experience only orthostatic hypotension. Other symptoms of catecholamine excess may include
The most common locations of abdominal sympathetic PGL is adjacent to the aorta. Surgery is the mainstay of treatment for abdominal PGL and represents the only chance of cure; approaches to resection may be either laparotomic or minimally invasive (endoscopic).
Minimally invasive adrenalectomy through transperitoneal approach or posterior retroperitoneal approach is the standard for removal of benign PHEO [3]. Safety and efficacy of minimally invasive adrenalectomy, in term of reduced pain,
Palliative radionuclide treatment may be considered in patients with metastatic disease and unresectable lesions. It can be performed using beta-emitting isotopes coupled with MIBG or somatostatine analogue [44]. External radiotherapy may be considered for treatment of inoperable PGL and especially for palliation of painful bone metastases.
Chemotherapy, aimed to tumor size reduction and control of symptoms due to catecholamine secretion, is usually reserved to patients with local advanced
The last decades have shown an enormous progress in the knowledge and clinical care of PGL. To date, germline mutations can be detected in at least one third of patients affected by PGL and strong genotype–phenotype associations have been recognized. Therefore, genetic testing and counseling should be considered in all PGL to provide the optimal outcome for patients and relatives. In fact, the improved knowledge of the genetic background contributed to a better understanding of the
The authors declare no conflict of interest. Search for clinical signs and symptoms that require biochemical testing for PGL Consider syndromic features related to hereditary PGL Use as initial biochemical test plasma or urinary metanephrines Choice of functional imaging should be based on location and genetic background Consider genetic testing in all patients: PGL phenotype is influenced by genotype Preoperative evaluation and medical preparation (including α-adrenoceptor blockade)Practice points
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