Familial Paraganglioma Syndrome
Paragangliomas (PGLs) and pheochromocytomas are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. In 2004, the World Health Organization characterized pheochromocytomas as tumors arising in the adrenal gland. (Refer to the Pheochromocytoma section of this summary for more information). Extra-adrenal neoplasms, referred to as PGLs, may arise in various sites from the glomera along the parasympathetic nerves or the paraganglia in the sympathetic trunk. PGLs may be found in the head and neck region, abdomen, or pelvis. PGLs found in the skull base or head and neck region are usually from parasympathetic paraganglia and rarely secrete catecholamines. Representing 3% of all PGLs, the tumors in the cervical region typically arise in the glomus cells, near the aortic body, along the vagal nerve, in the temporal bone, in the jugular fossa (middle ear space), or in the nose and parasinus. Tumors below the neck are most commonly located in the upper mediastinum, adrenal medulla (pheochromocytoma), or the urinary bladder. The reported incidence of these tumors in the general population is variable because they may be asymptomatic but ranges from 1 in 30,000 to 1 in 100,000 individuals. One autopsy study found a much greater incidence of 1 in 2,000 individuals, suggesting a high frequency of occult tumors. These tumors have an equal sex distribution.[5,6] PGLs can occur at any age but have the highest incidence between the ages of 40 and 50 years.[5,6]
PGLs may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in one of several hereditary PGL/pheochromocytoma syndromes. Up to 30% of patients presenting with apparently sporadic PGLs actually have a recognizable germline mutation in one of ten genes. One study found that in individuals with a single tumor and a negative family history, the likelihood of an inherited mutation was 11.6%, whereas another group detected mutations in 41% of such patients.
PGLs are typically slow-growing tumors, and some may be present for many years before coming to clinical attention. Conversely, a minority of these tumors may be malignant and present with a more aggressive clinical course. PGL and pheochromocytoma malignancy is defined by the presence of metastases at sites distant from the primary tumor in nonchromaffin tissue. Some experts view local invasion into surrounding tissue as an additional marker of malignancy.[9,10] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement. There are no reliable molecular, immunohistochemical, or genetic predictors to distinguish benign and malignant tumors, although some studies have shown a higher rate in SDHB carriers  and in individuals with larger tumors. Consequently, estimation of the rate of malignancy in PGLs is difficult; rates from 5% to 20% have been reported.[7,15,16] Common sites of metastases include bone, liver, and lungs.
PGLs arise from cells involved in the metabolism of catecholamines, but approximately 95% of tumors located in the head and neck region are parasympathetic and nonsecretory. Only tumors arising from the sympathetic neural chain have secretory capacity. The most recognizable PGL of the head and neck is the tumor arising from the carotid body. These tumors (glomus caroticum) present a significant challenge for surgeons because of their proximity to critical vessels and cranial nerves. The presence of the neoplasm in this critical location frequently results in the compromise of nearby structures; removal of the tumor may cause permanent impairment.
Clinical Diagnosis of PGL
A PGL may cause a variety of symptoms depending on the location of the tumor and whether the tumor has secretory capacity. PGLs of the head and neck are rarely associated with elevated catecholamines. Secretory PGLs may cause hypertension, headache, tachycardia, sweating, and flushing. Typically, nonsecretory tumors are painless, coming to attention only when growth of the lesion into surrounding structures causes a mass effect. Patients with a head or neck PGL may present with an enlarging lateral neck mass, hoarseness, Horner syndrome, pulsatile tinnitus, dizziness, facial droop, or blurred vision.
Imaging is the mainstay of diagnosis; the initial evaluation includes computed tomography of the neck and chest. PGLs typically appear homogeneous with intense enhancement after administration of intravenous contrast. Magnetic resonance imaging may also be used to distinguish the tumor from adjacent vascular and skeletal structures. On T2-weighted images, a tumor that is larger than 2 cm is likely to display a classic "salt and pepper" appearance, a reflection of scattered areas of signal void mingled with areas of high signal intensity from increased vascularity.
Nuclear imaging in combination with anatomic imaging may be useful for localization and determination of the extent of disease (multifocality vs. distant metastatic deposits). Functional imaging with 18F-dihydroxyphenylalanine (18F-DOPA), 18F-fluorodopamine, or positron emission tomography–computed tomography (PET-CT) may be particularly helpful in localizing head and neck tumors. Additionally, 123I-metaiodobenzylguanidine plus PET-CT is very specific for PGLs. Data suggest that the selection of PET tracer utilized for tumor localization should be centered on the patient’s genetic status, based on the metabolic activity of the various tumors. It has been suggested that patients with SDH and VHL mutations are more likely to have higher 18F-fluorodeoxyglucose activity, which is related to gene activation in response to hypoxia.[13,18] Some SDHB tumors only weakly concentrate 18F-DOPA, and patients with SDHx mutations may have false-negative results with such scans. Tumors with VHL mutations may likewise be missed with metaiodobenzylguanidine scans. (Refer to Table 7 for a list of various mutations and their optimal imaging modality.)
|Gene||Tumor Location||PGL Malignancy Rate||First-line Imaging Modality||Second-line Imaging Modality|
|FDG-MIBG = fluorodeoxyglucose-metaiodobenzylguanidine; 18F-DOPA = 18F-dihydroxyphenylalanine; 18F-FDA = 18F-fluorodopamine; 18F-FDG = 18F-fluorodeoxyglucose; 18F-FDOPA = 18F-fluoro-L-dihydroxyphenylalanine; 123I-MIBG = 123I-metaiodobenzylguanidine.|
|MA = majority (>50%); MI = minority (10%–50%); NR = not reported; R = rare (<10%).|
|aThese mutations are rare. There is very little information available about the best imaging modality for these mutations. This table will be updated as more information becomes available.|
|b18F-FDA is currently only available at the National Institutes of Health in Bethesda, MD, as an experimental tracer.|
|Adapted from Fishbein et al., Gimenez-Roqueplo et al., Bausch et al., and Taïeb et al..|
Genetics, Inheritance, and Genetic Testing
PGLs and pheochromocytomas can be seen as part of several well-described tumor susceptibility syndromes including von Hippel-Lindau, multiple endocrine neoplasia type 2, neurofibromatosis type 1, Carney-Stratakis syndrome, and familial paraganglioma (FPGL) syndrome. FPGL is most commonly caused by mutations in one of the following four genes: SDHA, SDHB, SDHC, and SDHD (collectively referred to as SDHx). The SDHx proteins form part of the succinate dehydrogenase (SDH) complex, which is located on the inner mitochondrial membrane and plays a critical role in cellular energy metabolism. Mutations in SDHB are most common, followed by SDHD and rarely SDHC and SDHA. More recently, mutations in the SDHAF2 (also called SDH5), TMEM127, and MAX genes have been described in FPGL, but these mutations are rare. The mechanism of tumor formation has remained elusive. One study suggests that SDHx-associated tumors display a hypermethylator phenotype that is associated with downregulation of important genes involved in the differentiation of neuroendocrine tissues.
The inheritance pattern of FPGL depends on the gene involved. While most families show traditional autosomal dominant inheritance, those with mutations in SDHAF2 and SDHD show almost exclusive paternal transmission of the phenotype. In other words, while the mutation can be passed down from mother or father, tumors will develop only if the mutation is inherited from the father.[25,26] In cases of FPGL not caused by SDHD or SDHAF2 mutations, first-degree relatives of an affected individual have a 50% chance of carrying the mutation and are at increased risk of developing PGLs. Because the family history can appear negative in families with lower penetrance mutations, it is important to offer genetic testing to all unaffected first-degree relatives once the mutation in the family has been identified.
Genetic testing for hereditary pheochromocytoma and PGL syndromes is largely based on published algorithms, whereby testing is performed stepwise based on factors such as tumor type and location, age at diagnosis, family history, and presence of malignancy.[7,28,29] This approach has allowed for cost-effective, targeted testing based on clinical features. Within the last several years, however, next-generation sequencing (NGS) technology has led to a dramatic decrease in the cost of genetic testing, and it is now possible to test for mutations in 10 to 30 genes for the same cost of testing two or three genes. These tests may be more appropriate for individuals and families who have an atypical presentation or overlapping clinical features. If the cost associated with multigene testing panels continues to decrease, it is likely that the testing algorithms may soon be obsolete for PGL and pheochromocytoma. A recent series analyzed 85 PGL and pheochromocytoma samples using an NGS panel test for the ten known PGL susceptibility genes and showed a sensitivity of 98.7%.
In FPGL, the type and location of tumors, age at onset, and lifetime penetrance vary depending on the gene that is mutated. While these correlations can help guide genetic testing and screening decisions, caution must be used given the high degree of variability seen in this condition. FPGL syndromes are among the rare inherited diseases in which genomic imprinting occurs. For example, the SDHD mutation is normally not activated when inherited from the mother, and the risk of FPGL syndromes is not increased. However, the mutation is turned on when the gene is inherited from the father, and the risk is increased.
SDHD mutations are mainly associated with an increased risk of parasympathetic PGLs. These are more commonly multifocal and located in the head and neck, while tumors in SDHB carriers are more often located in the abdomen.[31,32] One series showed a risk of 71% for a head and neck tumor in SDHD carriers, as opposed to a 29% risk in SDHB carriers. The lifetime risk for any PGL in any location in SDHD carriers was estimated to be as high as 77% by age 50 years in one series  and 90% by age 70 years in a second series. A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%. The rate of malignancy in SDHD carriers is lower than 5%.
Mutations in the SDHB gene are associated with sympathetic PGLs, although pheochromocytoma and parasympathetic PGLs also have been described. SDHB PGLs are more commonly located in the abdomen and mediastinum than in the head and neck. A review of 1,700 cases suggested a lifetime penetrance of 77%. The rate of malignancy is higher with SDHB than with the other SDH genes, with up to one-third of patients having malignant tumors in most series.[31,32] Mutations in SDHB have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), renal cell carcinoma, and papillary thyroid cancer.[31,32]
SDHC mutations are rare, accounting for an estimated 0.5% of all PGLs. In one series of 153 patients with multiple PGLs or a single PGL diagnosed before age 40 years, three (2%) had an SDHC mutation. Another series of 121 index cases from a head and neck PGL registry showed a mutation rate of 4% (5 of 121). SDHC mutations most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[7,36] Mutations in SDHB, SDHC, and SDHD can also cause Carney-Stratakis syndrome, which is characterized by the dyad of PGLs and GISTs.
Mutations in SDHA, SDAHF2, MAX, and TMEM127 have been described in a small number of cases. Collectively, they account for less than 2% to 3% of all cases. Although biallelic mutations in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome, it was not until recently that monoallelic mutations were linked to an increased risk of developing PGL. Only a handful of cases have been described. Tumors can develop in the head and neck, the adrenal, or in the abdomen (extra-adrenal).[39,40] The SDHAF2 gene encodes a protein that is responsible for flavination of SDHA and proper functioning of the SDHA subunit of the SDH complex. To date, mutations in SDHAF2 have been described in fewer than 20 cases and only with head and neck PGLs. The MAX gene was first described as a pheochromocytoma susceptibility gene in 2011 through exome sequencing of three unrelated cases. Three different germline mutations were identified, and a follow-up series of 59 cases by the same group identified an additional five mutations. The MAX protein is part of MYC-MAX-MXD1 network, which plays a key role in the development and progression of neural crest cell tumors. The TMEM127 gene is located on chromosome 2q11.2 and encodes a transmembrane protein known to be a negative regulator of mTOR, which regulates multiple cellular processes. A review of 23 patients with TMEM127 mutations showed that 96% (22 of 23) had a pheochromocytoma and 9% (2 of 23) had a PGL.
Before surgical removal of a PGL, all patients, including those without clinically apparent catecholamine excess, generally undergo biochemical testing to evaluate the secretory capacity of the tumor(s). This evaluation is best performed by measuring urine and/or plasma fractionated metanephrines (normetanephrine and metanephrine), which yields a higher sensitivity and specificity than directly measuring catecholamines (norepinephrine, dopamine, and epinephrine).[45-47] For patients whose plasma metanephrines levels are measured, blood is collected after an intravenous catheter has been inserted and the patient has been in a supine position for 15 to 20 minutes. Additionally, the patient should not have food or caffeinated beverages, smoke cigarettes, or engage in strenuous physical activity in the 8 to 12 hours before the blood draw.
Preoperative medical therapy is not essential for patients without evidence of catecholamine hypersecretion, although some advocate its use regardless of the results of hormonal testing. However, patients with catecholamine-secreting tumors unquestionably require some form of pharmacologic therapy to control hypertension for at least 10 to 14 days before surgery. Failure to adequately block the catecholamine excess can dramatically increase the risk of perioperative mortality from hypertensive crisis and lethal arrhythmias.[50,51]
The preoperative medical regimen may incorporate one of several drugs; in the absence of a randomized controlled trial comparing the various regimens, there is no universally recommended approach. The alpha-adrenoreceptor blocker phenoxybenzamine (Dibenzyline) is most frequently used to control blood pressure and expand the blood volume. Other alpha-blocking drugs have also been used with success, including prazosin, terazosin, or doxazosin; these drugs are more specific alpha-1 adrenergic competitive antagonists and have a shorter half-life than phenoxybenzamine.[52,53] The noncompetitive binding of phenoxybenzamine to the alpha receptors, coupled with its longer half-life, may result in a sustained effect of the drug, with some patients experiencing postoperative hypotension.[48,54] One study found that patients treated with sustained-release doxazosin had more stable perioperative hemodynamic changes and a shorter time interval to preoperative blood pressure control than did patients who received phenoxybenzamine.
Once the alpha blockade is initiated, expansion of the blood volume is often necessary, as these patients are typically volume contracted.[55,56] In addition to the vasodilatory effects from alpha blockade, volume expansion may be achieved by consuming a high-sodium diet and high fluid intake or a preoperative saline infusion. A clinical manifestation of adequate blockade is the symptom of nasal stuffiness or lightheadedness.
If heart-rate control is needed, a beta blocker may be used in conjunction with the alpha blocker 2 to 3 days before surgery. Beta blockers are not generally used alone, as unopposed alpha stimulation can result in exacerbation of hypertension. It is also important to note that some patients may have undiagnosed cardiac insufficiency from the chronic stimulation by catecholamines; expansion of the blood volume and use of beta blockers may precipitate acute heart failure.
Calcium channel blockers such as nicardipine or nifedipine also have been employed to control the hypertension preoperatively. A calcium channel blocker may be used in conjunction with alpha and beta blockade for refractory hypertension or used alone as a second-line agent for patients with intolerable side effects from alpha blockade.
Surgical resection is the treatment of choice for PGLs. After appropriate preoperative pharmacologic preparation (see above), a successful resection involves several key elements. A thorough medical history and physical exam includes obtaining information about the patient's autonomic nervous system, including the presence of tachyarrhythmias or elevated blood pressure. Inappropriate preoperative preparation, induction of anesthesia, tumor manipulation, or other stimulation can result in massive intraoperative outpouring of catecholamines with subsequent hypertensive crisis and possible stroke, arrhythmia, or myocardial infarction.
Accurate preoperative imaging identifies vascularity and enables assessment of peritumoral invasion. En bloc resection with possible vascular reconstruction may be part of the preoperative plan. The arterial supply frequently includes small tributaries from the aorta, renal artery, and the inferior phrenic artery or iliac arteries. The arterial supply should be studied preoperatively to inform the surgical planning strategy. This is particularly critical because unexpected intraoperative vascular findings can be life threatening.
Central line access is critical so that intravenous fluids and medications can be rapidly administered. Communication between the operating surgeon and the anesthesiologist is necessary during the procedure. Before the tumor is removed, blood pressure is controlled with vasodilators, nitroprusside, and/or calcium channel blockers. Upon ligation of the vessels, pressor support may be required.
Adequate exposure of the tumor is important. PGLs are commonly located in the para-aortic retroperitoneal sympathetic chain above the aortic bifurcation, below the takeoff of the inferior mesenteric artery (organ of Zuckerkandl), or near the dome of the bladder.[58,59] Means of exposure using the transperitoneal approach are based on the anatomic location of the tumor. Proximal and distal control of blood vessels is critical. Vascular reconstruction can be considered in selected patients with local, large-vessel invasion, if such reconstruction will result in complete tumor extirpation. Dissection around the tumor without capsular rupture or tumor manipulation is important. Ideally, the adrenal vein is ligated early in the dissection to prevent release of catecholamines if the tumor is manipulated. However, this may not be possible in the case of a large tumor. When direct visualization of the tumor is apparent, clear differentiation between the surrounding tissue planes is necessary. Commonly, malignant PGLs have a dense fibrous capsule that is adherent to surrounding vascularity, which can make a complete resection difficult. Regional lymph nodes are commonly involved with the tumor, and if suspected preoperatively or noted intraoperatively, a regional lymphadenectomy should be performed. En bloc resection of surrounding organs is rarely necessary.
Open resection and laparoscopic approaches both are safe. There is no evidence that the carbon dioxide insufflation triggers a catecholamine crisis. Open resection is recommended for tumors larger than 6 cm because of the increased risk of technical difficulty within the confined and closed space created with only carbon dioxide insufflation during laparoscopy. Additionally, there is an increased risk of tumor rupture with laparoscopic approaches, and they are inferior regarding nodal sampling. However, patients experience faster resolution of postoperative ileus; decreased analgesic requirements; a shorter hospital stay; and shorter convalescence, with a quicker return to normal activity with laparoscopic approaches. Direct access to the para-aortic region can be achieved with the posterior approach. Robotic assistance has improved the technique by offering a 3-dimensional, magnified view of the anatomy. For an anterior open resection, incisions are based on the tumor location. Cardiopulmonary bypass may be required for tumors in the middle mediastinum because they usually involve the left atrium. Posterior mediastinal tumors may require posterior thoracotomy. Tumors located in the bladder may require partial cystectomy. Regardless of tumor size, all patients should undergo evaluation for metastasis.
In summary, surgical resection is the treatment of choice for patients with PGL. If the disease is limited at the time of diagnosis, surgical resection can be undertaken with curative intent. If disease is more extensive or locally recurrent, then surgical intervention is undertaken for tumor debulking and palliation. In patients with noncurable disease, surgery of the primary tumor and/or metastases could reduce hormone secretion and may be appropriate to prevent complications related to a critical anatomical location. Surgery should be performed in referral centers and by expert hands. Long-term follow-up may identify metastases years after the initial diagnosis.
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