Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version - National Cancer Institute

Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)–Health Professional Version

Familial Pheochromocytoma and Paraganglioma Syndrome

Introduction

Paragangliomas (PGLs) and pheochromocytomas (PHEOs) are rare tumors arising from chromaffin cells, which have the ability to synthesize, store, and secrete catecholamines and neuropeptides. Individuals may present with secondary hypertension. In 2004, the World Health Organization characterized adrenal gland tumors as PHEOs.[1] The term paraganglioma is reserved for non-adrenal (or extra-adrenal) neoplasms and may arise in various sites from the paraganglia along the parasympathetic nerves or the sympathetic trunk. PGLs may be found in the head and neck region, abdomen, or pelvis. Only those arising from sympathetic neural chains have secretory capacity. PGLs found in the skull base or head and neck region typically arise in the glomus cells, near the carotid body, along the vagal nerve or jugular fosse, and are usually from parasympathetic paraganglia and therefore rarely secrete catecholamines.[2,3] The most recognizable tumors are found at the carotid body. PGLs below the neck are most commonly located in the upper mediastinum or the urinary bladder.[3] 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.[3] One autopsy study found a much greater incidence of 1 in 2,000 individuals, suggesting a high frequency of occult tumors.[4] PGLs have an equal sex distribution and can occur at any age but have the highest incidence between the ages of 40 and 50 years.[5,6]

Clinical Description

PGLs and PHEOs may occur sporadically, as a manifestation of a hereditary syndrome, or as the sole tumor in one of several hereditary PGL/PHEO syndromes.

PGLs and PHEOs 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 PHEO malignancy is defined by the presence of metastases at sites distant from the primary tumor in nonchromaffin tissue. Common sites of metastases include bone, liver, and lungs.[1]

There are no reliable molecular, immunohistochemical, or genetic predictors to distinguish benign and malignant tumors,[7] although some studies have shown a higher malignancy rate in SDHB carriers [8] and in individuals with larger tumors.[9] Some experts view local invasion into surrounding tissue as an additional marker of malignancy.[10,11] Others have disagreed with this classification because locally invasive tumors tend to follow a more indolent course than tumors with distant metastatic involvement.[12] Consequently, estimation of the rate of malignancy in PGLs is difficult; rates ranging from 5% to 20% have been reported.[13-16]

Clinical Diagnosis of PGL and PHEO

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 and PHEOs 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.[1]

Patients with clinically apparent catecholamine excess generally undergo biochemical testing to evaluate the secretory capacity of the tumor(s).[17] 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).[18-20] 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.[21] 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.[21]

Imaging of PGLs is the mainstay of diagnosis; the initial evaluation includes computed tomography (CT) of the neck and chest. Magnetic resonance imaging (MRI) also has utility for the head and neck. PGLs typically appear homogeneous with intense enhancement after administration of intravenous contrast. MRI 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.[22]

Nuclear imaging, particularly somatostatin receptor scintigraphy (SRS) in combination with anatomic imaging, may be useful for localization and determination of the extent of disease (multifocality vs. distant metastatic deposits).[23] Benign tumors are reported to be more sensitive to SRS than iodine I 123-metaiodobenzylguanidine (123I-MIBG) imaging. Sensitivity is highest for the head and neck region compared with abdomen PGLs or PHEOs (91% vs. 40% and 42%, respectively).[24] SRS has been reported to be superior to MIBG in detecting metastatic tumors (95% vs. 23%, respectively).[24] 123I-MIBG, however, is highly sensitive for PHEO [24] and positron emission tomography–computed tomography (PET-CT) is very specific for PGLs. Functional imaging for PGLs and/or PHEOs with fluorine F 18-dihydroxyphenylalanine (18F-DOPA), 18F-fluorodopamine, or PET-CT may be particularly helpful in localizing head and neck tumors. Data suggest that the selection of PET tracer utilized for tumor localization should be centered on the patient’s genetic status, on the basis of the metabolic activity of the various tumors.[8] It has been suggested that patients with SDHx and VHL pathogenic variants are more likely to have higher 18F-fludeoxyglucose activity, which is related to gene activation in response to hypoxia.[8,25] Some SDHB tumors only weakly concentrate 18F-DOPA, and patients with SDHx pathogenic variants may have false-negative results with such scans. Gallium Ga 68-DOTATATE PET-CT shows promise as a potential imaging modality for determining the extent of disease in patients with metastatic involvement.[26] Tumors with VHL pathogenic variants may likewise be missed with MIBG scans.[8]

Imaging of PHEOs usually consists of a dedicated CT of the adrenal gland. When biochemical screening in an individual who has or is at risk of multiple endocrine neoplasia type 2 (MEN2) suggests PHEO, localization studies, such as MRI or CT, can be performed.[27] Confirmation of the diagnosis can be made using iodine I 131-MIBG scintigraphy or PET imaging.[27-30]

Genetics, Inheritance, and Genetic Testing

A significant proportion of individuals presenting with apparently sporadic PHEO or PGL are carriers of germline pathogenic variants. Up to 33% of patients with apparently sporadic PHEO, and up to 40% of patients with apparently sporadic PGLs, actually have a recognizable germline pathogenic variant in one of the known PGL/PHEO susceptibility genes.[14,31-35] One study found that in individuals with a single tumor and a negative family history, the likelihood of an inherited pathogenic variant was 11.6%,[14] whereas other groups detected pathogenic variants in 41% of such patients.[35,36] In a retrospective review of 55 patients younger than 21 years who had PGL/PHEO and were referred to the National Cancer Institute, 80% of patients had a germline pathogenic variant.[37] (Refer to the Pheochromocytoma and Paraganglioma section in the PDQ summary on Unusual Cancers of Childhood Treatment for more information about PGL/PHEO in children.) For example, even among carriers of SDHB pathogenic variants, there is low penetrance and delayed onset of disease, which may further obscure the hereditary nature of the disease.[38] As such, all patients with PHEO or PGL, even those with apparently sporadic tumors, may be considered for genetic testing because of the high frequency of pathogenic variants associated with these conditions.[39]

PGLs and PHEOs can be seen as part of several well-described tumor susceptibility syndromes including von Hippel-Lindau (VHL), MEN2, neurofibromatosis type 1, Carney-Stratakis syndrome, and familial paraganglioma (FPGL) syndrome. FPGL is most commonly caused by pathogenic variants 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.[40] Pathogenic variants in SDHB are most common, followed by SDHD and rarely SDHC and SDHA. More recently, pathogenic variants in the SDHAF2 (also called SDH5), TMEM127, and MAX genes have been described in FPGL/PHEO,[41-44] but these variants 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.[45]

The inheritance pattern of FPGL depends on the gene involved. While most families show traditional autosomal dominant inheritance, those with pathogenic variants in SDHAF2 and SDHD show almost exclusive paternal transmission of the phenotype. In other words, while the pathogenic variant can be passed down from mother or father, tumors will develop only if the pathogenic variant is inherited from the father.[46,47] In cases of FPGL not caused by SDHD or SDHAF2 pathogenic variants, first-degree relatives (FDRs) of an affected individual have a 50% chance of carrying the pathogenic variant and are at increased risk of developing PGLs. Because the family history can appear negative in families with lower penetrance pathogenic variants, it is important to offer genetic testing to all unaffected FDRs once the pathogenic variant in the family has been identified.

Genetic testing for hereditary PHEO and PGL syndromes is largely based on published algorithms,[39] whereby testing is performed stepwise on the basis of factors such as tumor type and location, age at diagnosis, family history, and presence of malignancy.[14,48,49] This approach has allowed for cost-effective, targeted testing on the basis of 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 testing for pathogenic variants in 10 to 30 genes for the same cost of testing two or three genes is now possible. 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, the testing algorithms may soon be obsolete for PGL and PHEO. A 2013 series analyzed 85 PGL and PHEO samples using an NGS panel test for the ten known PGL susceptibility genes; the NGS assay and analysis showed a sensitivity of 98.7%.[50] Screening through a multigene panel moderately increases the detection rate. In a small series of 87 patients with PHEO, 25.3% of individuals (22 of 87) were found to have germline pathogenic variants on a screening panel that included ten PGL/PHEO-associated genes; 11.7% had germline pathogenic variants in VHL, 6.8% in RET, 2.3% in SDHD, 2.3% in MAX, 1.1% in SDHB, and 1.1% in TMEM127.[51] Apparently sporadic tumors were present in 74.7% of patients (65 of 87).

Genotype-Phenotype Correlations

In FPGL/PHEO, the type and location of tumors, age at onset, and lifetime penetrance vary depending on the genetic variant. 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/PHEO syndromes are among the rare inherited diseases in which genomic imprinting occurs. For example, the SDHD pathogenic variant is normally not activated when inherited from the mother, and the risk of FPGL/PHEO syndromes is not increased. However, the pathogenic variant is turned on when the gene is inherited from the father, and the risk is increased.

SDHD pathogenic variants 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.[52,53] Multiple series showed a risk of 71% for a head and neck tumor in SDHD carriers, as opposed to a 27% to 29% risk in SDHB carriers.[16,52] 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 [52] and 90% by age 70 years in a second series.[53] A review of more than 1,700 cases reported in the literature provided similar estimates, suggesting a lifetime penetrance of 86%.[54] The rate of malignancy in SDHD carriers is lower than 5%.[54]

Pathogenic variants in the SDHB gene are associated with sympathetic PGLs, although PHEO 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%.[54] However, many early studies examining penetrance were subject to ascertainment bias due to sampling of highly suggestive individuals affected at young ages, with limited inclusion of asymptomatic pathogenic variant carriers. Family-based and population-based studies have found lower penetrance estimates, ranging from 9% to 35% by age 50 years.[38,55-58] Other studies have estimated lifetime penetrance to be 42% to 50%.[58,59] There is some evidence that the penetrance in SDHB carriers may be lower in females than in males.[59] 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.[52,53] Pathogenic variants in SDHB have also been associated with several other tumors and malignancies, including gastrointestinal stromal tumors (GISTs), renal cell carcinoma, and papillary thyroid cancer.[52,53]

SDHC pathogenic variants are rare, accounting for an estimated 0.5% of all PGLs.[54] In one series of 153 patients with multiple PGLs or a single PGL diagnosed before age 40 years, three (2%) had an SDHC pathogenic variant.[32] Another series of 121 index cases from a head and neck PGL registry showed a pathogenic variant rate of 4% (5 of 121).[60] SDHC pathogenic variants most commonly cause head and neck PGLs but have been seen in a small number of patients with abdominal PGLs.[14,61] Pathogenic variants in SDHB, SDHC, and SDHD can also cause Carney-Stratakis syndrome, which is characterized by the dyad of PGLs and GISTs.[62]

Pathogenic variants in SDHA, SDHAF2, MAX, and TMEM127 have also been described; collectively, they account for less than 2% to 3% of all cases. Although biallelic pathogenic variants in SDHA have long been known to cause the autosomal recessive condition inherited juvenile encephalopathy/Leigh syndrome,[63] it was not until recently that monoallelic pathogenic variants were linked to an increased risk of developing PGL. One series showed a 7.6% incidence of SDHA pathogenic variants in a cohort of 393 patients with PGL in the Netherlands.[64] Tumors most commonly develop in the head and neck, followed by the adrenal glands and abdomen (extra-adrenal).[65,66] In the same series from the Netherlands,[64] the estimated penetrance for non-index pathogenic variant carriers was 10% by age 70 years. Initially, pathogenic variants in SDHAF2 were described only in head and neck PGLs.[44] The MAX gene was first described as a PHEO susceptibility gene in 2011 through exome sequencing of three unrelated cases.[41] Three different germline pathogenic variants were identified, and a follow-up series of 59 cases by the same group identified an additional five variants. The MAX protein plays a key role in the development and progression of neural crest cell tumors.[67] 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 pathogenic variants showed that 96% (22 of 23) had a PHEO and 9% (2 of 23) had a PGL.[54]

A study of an additional 58 patients from the European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group more than doubles the number of previously reported carriers of the rare predisposition genes SDHA (n = 29), SDHAF2 (n = 1), MAX (n = 8), and TMEM127 (n = 20).[68] The study identified malignant disease in 12% of SDHA pathogenic variant carriers and 10% of TMEM127 carriers, which is significantly higher than previous estimates. Extra-adrenal tumors were common in the cohort (48%), particularly in SDHA carriers (79%) who had an overrepresentation of head and neck tumors (44%). However, no GIST tumors were identified in SDHA carriers in this cohort, compared with frequent reports in previously identified cohorts. SDHA-related tumors occurred in patients as young as 8 years. Tumors associated with MAX pathogenic variants were almost all in the adrenal glands, and frequently bilateral. Overall, penetrance of developing a PGL/PHEO by age 40 years was estimated to be 73% for MAX pathogenic variant carriers, 41% for TMEM127 carriers, and 39% for SDHA carriers. Penetrance was also calculated for pathogenic variant–positive relatives and was significantly lower for these individuals (13%) compared with index patients for SDHA carriers, but not significantly different for MAX or TMEM127 probands and nonprobands. It is important to remember that these relatively small studies are prone to selection and ascertainment biases, as mentioned above. For example, only 22% of family members from this cohort had cascade screening, which affects penetrance calculations. Additionally, the high rates of metastatic disease could represent ascertainment bias of a tertiary care center, and the lack of GIST tumors could be because this was a PGL/PHEO-specific registry, and therefore might not capture the full spectrum of related tumors.[69]

Surveillance

Patients with an identified germline pathogenic variant in one of the SDH genes are at a significantly increased risk of developing PGLs, PHEOs, renal tumors, and GISTs. PHEOs and PGLs typically have a slow growth pattern, but unchecked growth can lead to mass effect and, ultimately, neurologic compromise. Further, although most of these tumors are benign, some may undergo malignant transformation. As such, periodic screening for interval development of a tumor is of critical importance because early detection and removal can minimize risk to the patient. Although limited studies have been performed to delineate the ideal protocol, total-body MRI has been proposed as a reasonable method for screening because of its high sensitivity and minimal radiation exposure.[39,70] In one study, 37 carriers of SDHx pathogenic variants underwent annual biochemical testing and annual or biennial whole-body MRI beginning at age 10 years.[71] This screening protocol identified six tumors in five patients. The sensitivity of MRI was 87.5%, and the specificity was 94.7%. The sensitivity of biochemical testing was significantly lower at 37.5%, with a specificity similar to MRI at 94.9%.[71] A retrospective study of 157 patients evaluated a rapid contrast-enhanced angio-MRI protocol for the detection of head and neck paragangliomas in carriers of SDH pathogenic variants.[72] This protocol had a high sensitivity and specificity of 88.7% and 93.7%, respectively.

Although the optimal imaging protocol for surveillance in carriers of SDH pathogenic variants remains unclear, annual biochemical testing and clinical surveillance may be considered. Biochemical testing can be performed by measuring plasma-free metanephrines/catecholamines or 24-hour urinary excretion of fractionated catecholamines (including methoxytyramine, a dopamine metabolite, if available). Clinical surveillance may include physical examination and blood pressure measurement. Clinical surveillance and biochemical testing may begin between ages 5 years and 10 years, or 10 years earlier than the earliest age at diagnosis in the family.[73,74]

Level of evidence: 4

Interventions

Preoperative management

Medical management is the bridge to surgical resection of PGLs/PHEOs. 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.[21] The aim of pharmacologic therapy is to control hypertension for at least 10 to 14 days before surgery.[75] Management is aimed at preventing catecholamine-induced complications, even in patients who may not present with preoperative hypertension, to avoid intraoperative hypertensive crisis, cardiac arrhythmias, pulmonary edema, and cardiac ischemia. Failure to adequately block the catecholamine excess can dramatically increase the risk of perioperative mortality from hypertensive crisis and lethal arrhythmias and cause hypotensive crisis after tumor removal.[76,77]

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.[21] 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.[78,79] 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.[21,80] 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.[80]

Once the alpha blockade is initiated, expansion of the blood volume is often necessary, as these patients are typically volume contracted.[81,82] 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.

Calcium channel blockers such as nicardipine or nifedipine also have been employed to control the hypertension preoperatively.[83] 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.[21]

Consideration of preoperative imaging is warranted if a pathogenic variant has been identified, as it may alter the surgical plan and approach.[37] (Refer to the Clinical Diagnosis of PGL and PHEO section of this summary for more information about imaging modalities.)

Surgery

Surgical resection is the treatment of choice for PGL and PHEO. Both open resection and laparoscopic approaches are safe, but if feasible, laparoscopic removal is preferred.[73,84] Open resection is commonly recommended for large tumors (>6 cm–7 cm) because of the increased risk of technical difficulty within the confined space of laparoscopy. Means of exposure and approach are based on the anatomic location of the tumor. Direct access to the adrenal and para-aortic region can be achieved with the posterior approach. It is direct, safe, and efficient.[85] Adequate exposure of the complete tumor is important for complete removal. Robotic assistance can be utilized in select cases because it offers a three-dimensional, magnified view of the anatomy.[86] The efficacy and safety of posterior retroperitoneoscopic adrenalectomy is established, but ongoing studies are examining the relevance of this approach in familial syndromes (refer to NCT02618694).

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.[87,88] Malignant PGLs have a dense fibrous capsule that may be adherent to surrounding vascularity, which can make complete resection difficult.[88] Regional lymph nodes may be involved with malignant tumors, and if suspected preoperatively or noted intraoperatively, a regional lymphadenectomy may be performed.

Genetic testing is best performed before the initial surgery to inform the risk of recurrent or contralateral disease and to guide the extent of resection (e.g., whether to preserve the cortex) because synchronous or metachronous bilateral disease is quite common in hereditary PHEO. Preoperative knowledge of a germline pathogenic variant significantly affects variables associated with a cortical-sparing adrenalectomy. Preserving the cortex is important in patients with a known pathogenic variant because they are at risk of developing a contralateral tumor. Cortical sparing reduces the possibility of future adrenal insufficiency with contralateral adrenalectomy. This consideration must be weighed against the high risk of malignancy in SDHB carriers. In one study cohort of 108 patients, 33% of patients with a germline pathogenic variant did not have a family history of an inherited syndrome, and 36% of the patients with SDHB germline pathogenic variants had no family history and no previous history of PGL/PHEO on presentation.[89] In one retrospective series that spanned nearly 50 years, 15 of the 49 patients (30%) who presented with a unilateral PHEO and underwent unilateral total adrenalectomy developed PHEO in the contralateral gland at a median of 8.2 years (range, 1–20 y) after initial diagnosis.[90] Of the 15 patients who developed PHEO in the contralateral gland, 8 had MEN2A, 2 had MEN2B, 2 had VHL, and 1 had familial PHEO. The risk of developing a contralateral tumor increased over time, with 25% of patients developing tumors after a median of 6 years and 43% after a median of 32 years. Cortical-sparing surgery is an attractive option because it minimizes the risk of adrenal insufficiency and the need for lifelong steroid supplementation. In large series of patients, cortical-sparing surgery has a 3% to 7% recurrence rate after cortical preservation versus a 2% to 3% recurrence rate after total resection (recurrence in the adrenal bed).[90,91] The frequency of steroid dependence in both studies was lower in patients who underwent cortical-sparing techniques than in patients who did not (57% compared with 86%). One of 39 patients (3%) developed adrenal insufficiency after a cortical-sparing procedure; 5 of 25 patients (20%) developed adrenal insufficiency after total adrenalectomy.[90] These study authors recommend cortical-sparing surgery as a viable option for patients with hereditary PHEO, including patients who initially present with seemingly unilateral disease.

Level of evidence: 5

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