Clinical characteristics.

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.

Diagnosis/testing.

The diagnosis of a hereditary PGL/PCC syndrome should be suspected in any individual with a diagnosis of paraganglioma or pheochromocytoma. A diagnosis of hereditary PGL/PCC is strongly suspected in an individual with multiple, multifocal, recurrent, or early-onset paraganglioma or pheochromocytoma and/or a family history of paraganglioma or pheochromocytoma. The diagnosis is established in a proband by identification of a germline heterozygous pathogenic variant in MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 on molecular genetic testing.

Management.

Treatment of manifestations: For secretory PGL/PCC, treatment requires using medications for alpha adrenergic receptor blockade followed by surgery. For nonsecretory HNPGLs, surgical resection should be considered only after a detailed analysis of benefits and risks of a surgical procedure. All individuals with HNPGL should be evaluated for catecholamine excess before surgical resection, which, if present, can suggest an additional primary PGL/PCC. Watchful waiting or radiation therapy are options for HNPGLs. PGL/PCCs identified in individuals known to have SDHB pathogenic variants may benefit from resection over radiation or watchful waiting because of the higher risk for metastatic disease.

Prevention of secondary complications: Early detection through surveillance and removal of tumors may prevent or minimize complications related to mass effects, unregulated catecholamine secretion, and metastatic disease.

Surveillance: Beginning between ages six and eight years, individuals at risk for hereditary PGL/PCC syndromes should have annual biochemical and clinical surveillance for signs and symptoms of PGL/PCC and biennial full-body MRI examination. Consider endoscopic evaluation for gastrointestinal stromal tumors in individuals with unexplained gastrointestinal symptoms.

Agents/circumstances to avoid: Hypoxic conditions (e.g., living at high altitude, cigarette smoking) may increase tumor incidence and promote tumor growth, although data are extremely limited.

Evaluation of relatives at risk: First-degree relatives of an individual with a known MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, or TMEM127 pathogenic variant should be offered molecular genetic testing to clarify their genetic status to improve diagnostic certainty and reduce the need for costly screening procedures in those who have not inherited the pathogenic variant.

Genetic counseling.

The hereditary PGL/PCC syndromes are inherited in an autosomal dominant manner. Pathogenic variants in SDHD demonstrate parent-of-origin effects and generally cause disease only when the pathogenic variant is inherited from the father. Pathogenic variants in SDHAF2 and possibly MAX exhibit parent-of-origin effects similar to those of pathogenic variants in SDHD. A proband with a hereditary PGL/PCC syndrome may have inherited the pathogenic variant from a parent or, rarely, have a de novo pathogenic variant; the proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with a hereditary PGL/PCC syndrome-causing pathogenic variant has a 50% chance of inheriting the pathogenic variant. An individual who inherits an SDHD pathogenic variant from his/her mother is at a very low but not negligible risk of developing disease. An individual who inherits an SDHD pathogenic variant from his/her father is at high risk of manifesting PGL/PCC. If the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes should be suspected in any individual with a paraganglioma or pheochromocytoma, particularly individuals with the following findings [Young 2011, Lenders et al 2014]:

• Tumors that are:
  • Multiple (i.e., >1 paraganglioma or pheochromocytoma), including bilateral adrenal pheochromocytoma
  • Multifocal with multiple synchronous or metachronous tumors
  • Recurrent
  • Early onset (i.e., age <45 years)
  • Extra-adrenal
  • Metastatic
• A family history of paraganglioma or pheochromocytoma, or relatives with unexplained or incompletely explained sudden death
  Note: Many individuals with hereditary PGL/PCC syndrome may present with a solitary tumor of the skull base or neck, thorax, abdomen, adrenal, or pelvis and no family history of paraganglioma or pheochromocytoma.

The following clinical and laboratory features suggest a paraganglioma or pheochromocytoma.

Clinical features

• Signs and symptoms of catecholamine excess (e.g., classic signs and symptoms of sustained or paroxysmal elevations in blood pressure, headache, palpitations, arrhythmia, profuse sweating, apprehension or anxiety, and non-classic signs and symptoms of pallor, nausea/vomiting, and sudden change in glycemic control)
• Symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition.
• Palpable abdominal mass
• Enlarging mass of the skull base or neck
• Compromise of cranial nerves (VII, IX, X, XI) and sympathetic nerves in the head and neck area (e.g., hoarseness, dysphagia, soft palate paresis, Horner syndrome)
• Tinnitus

Laboratory findings. Elevated fractionated metanephrines and/or catecholamines in plasma and/or a 24-hour urine sample can include any of the following:

• Epinephrine (adrenaline) and its major metabolite metanephrine
• Norepinephrine (noradrenaline) and its major metabolite normetanephrine
• Dopamine and its major metabolite 3-methyoxytyramine

Note: (1) Measurement of fractionated metanephrine concentrations in plasma or urine is preferred, as it is more sensitive than measurement of catecholamine concentrations [Young 2011]. (2) False positive results may be reduced by follow-up testing for 24-hour urine fractionated metanephrines when plasma normetanephrine concentrations are less than fourfold above the reference range [Algeciras-Schimnich et al 2008]. (3) The secretion of epinephrine with little norepinephrine excess suggests an adrenal pheochromocytoma, which may be associated with multiple endocrine neoplasia type 2 [Young 2011].

Establishing the Diagnosis

The diagnosis of hereditary PGL/PCC should be strongly suspected in an individual with multiple, multifocal, recurrent, or early-onset paraganglioma or pheochromocytoma and/or a family history of paraganglioma or pheochromocytoma.

The diagnosis of hereditary PGL/PCC syndromes is established in a proband with a germline heterozygous pathogenic variant in one of the genes listed in Table 1.

Clinical Description

In individuals with hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes, tumors arise within the paraganglia – collections of neural crest cells distributed along the paravertebral axis from the base of the skull to the pelvis – as well as in some visceral locations. The 2017 World Health Organization (WHO) Classification of Endocrine Tumours classifies paragangliomas/pheochromocytomas by location and (directly or indirectly) secretory status [Lloyd et al 2017].

Paragangliomas (paraganglion tumors) arise from neuroendocrine tissues (paraganglia) distributed along the paravertebral axis from their predominant location at the skull base to the pelvis.

Head and neck paragangliomas (HNPGLs) and those in the upper mediastinum are primarily associated with the parasympathetic nervous system and typically do not secrete catecholamines or other hormones. Approximately 5% of HNPGLs secrete catecholamines. The rare secretory tumors in the head and neck area are either a subset of carotid body tumors or arise from the cervical sympathetic chain. Most HNPGLs do not metastasize, although there are many exceptions. Clinical complications of HNPGLs are typically the result of mass effect:

• Carotid body paragangliomas often present as asymptomatic, enlarging lateral neck masses. (The carotid bodies are located at or near the bifurcations of the carotid arteries, in the lateral upper neck at approximately the level of the fourth cervical vertebra.) Affected individuals may experience mass effects, including cranial nerve and sympathetic chain compression, with resulting neuropathies. On physical examination masses are vertically (but not horizontally) fixed; bruits and/or thrills may be present.
• Vagal paragangliomas present in a manner similar to carotid body paragangliomas. Signs and symptoms include neck masses, hoarseness, pharyngeal fullness, dysphagia, dysphonia (impaired use of the voice), pain, cough, and aspiration. Dysphonia may be caused by mass effects within the throat or by pressure on nerves supplying the vocal cords or tongue.
• Jugulotympanic paragangliomas may present with pulsatile tinnitus, hearing loss, and other lower cranial nerve abnormalities. Blue-colored, pulsatile masses may be visualized behind the tympanic membrane on otoscopic examination [Gujrathi & Donald 2005].

Paragangliomas in the lower mediastinum, abdomen, and pelvis are typically associated with the sympathetic nervous system and usually secrete catecholamines. Sympathetic paragangliomas located along the paravertebral axis (and not in the adrenal gland) are called "extra-adrenal sympathetic paragangliomas." Extra-adrenal sympathetic paragangliomas have an increased likelihood of malignant transformation [Ayala-Ramirez et al 2011].

Pheochromocytomas are catecholamine-secreting paragangliomas confined to the adrenal medulla. Malignancy is less likely in pheochromocytomas but certainly does occur (see Genotype-Phenotype Correlations). Pheochromocytomas are also known as adrenal chromaffin tumors.

Note: "Chromaffin cells/tumors" is another term for any sympathetic (catecholamine-secreting) neuroendocrine cells/tumors regardless of location. "Chromaffin" refers to the brown-black color that results from oxidization and polymerization of catecholamines contained in the cells/tumors by chromium salts (e.g., potassium dichromate).

Signs and symptoms of paraganglioma and pheochromocytoma are similar in individuals with hereditary PGL/PCC syndromes and individuals with sporadic (i.e., not inherited) tumors, most often coming to medical attention in the following four clinical settings:

• Signs and symptoms of catecholamine excess, including episodic or sustained elevations in blood pressure and pulse, headaches, palpitations (perceived episodic, forceful, often rapid heartbeat), arrhythmias, excessive sweating, pallor, apprehension, and anxiety. Nausea, emesis, fatigue, sudden alteration in glycemic control, and weight loss can also be seen. Paroxysmal symptoms may be triggered by changes in body position, increases in intra-abdominal pressure, medications (e.g., metoclopramide), anesthesia induction, exercise, or micturition in individuals with urinary bladder paragangliomas. Urinary bladder paragangliomas may also be accompanied by painless hematuria.
• Signs and symptoms related to mass effects from the neoplasm (particularly HNPGLs) which can compromise cranial nerves (e.g., VII, IX, X, XI) and sympathetic nerves in the head and neck area leading to hoarseness, dysphagia, soft palate paresis, Horner syndrome, and/or tinnitus
• Incidentally discovered mass on MRI/CT performed for other reasons
• Screening of at-risk relatives

Biochemical features of PGL/PCC. Catecholamines and metanephrines secreted by PGL/PCC can be any of the following:

• Epinephrine (adrenaline) and its major metabolite metanephrine
• Norepinephrine (noradrenaline) and its major metabolite normetanephrine
• Dopamine and its major metabolite 3-methoxytyramine

Plasma chromogranin A, not a catecholamine but another substance often secreted by PGL/PCC, can sometimes be useful for diagnosis. Its specificity is not great, however, as many other medical conditions (e.g., liver and kidney disease; gastrointestinal conditions such as IBS and colon cancer; other malignancies) and medications (e.g., proton pump inhibitors) can elevate plasma chromogranin A levels.

Radiographic features of PGL/PCC. Individuals with hereditary PGL/PCC syndromes should be evaluated by imaging for tumor localization. CT rather than MRI is often the imaging modality of choice, given its excellent spatial resolution of the thorax, abdomen, and pelvis [Lenders et al 2014]. MRI is a better option in individuals for whom radiation exposure must be limited, such as pregnant women, and for lifelong screening for biochemically silent PGL/PCC and other manifestations in those asymptomatic individuals with known germline pathogenic variants.

• Paragangliomas can be identified anywhere along the paravertebral axis from the skull base to the pelvis, including the para-aortic sympathetic chain, as well as some other visceral locations. Common sites of neoplasia are near the renal vessels and in the organ of Zuckerkandl (chromaffin tissues near the origin of the inferior mesenteric artery and the aortic bifurcation). A less common site is within the urinary bladder wall.
• PGL/PCC tumors usually exhibit high signal intensity on T₂-weighted MRI and have no loss of signal intensity on in- and out-of-phase imaging, which helps distinguish pheochromocytomas from benign adrenal cortical adenomas. On CT examination these tumors are characterized by heterogeneous appearance with cystic areas, high unenhanced CT attenuation (density, Hounsfield units >10), increased vascularity on contrast-enhanced CT, and slow contrast washout.
• Multiple tumors can be present.
• Whole-body MRI with targeted MRI for positive tumors may be a reasonable approach for both diagnosis and monitoring of individuals with hereditary PGL/PCC syndromes. This strategy minimizes radiation exposure associated with CT scanning, while taking advantage of the high sensitivity of T_2-weighted MRI.
• Digital subtraction angiography (DSA) is sensitive for the detection of small paragangliomas and can be diagnostically definitive. DSA is essential if preoperative embolization or carotid artery occlusion is to be performed.

Distinguishing benign and malignant PGL/PCCs. No reliable pathology studies are available to distinguish a primary benign PGL/PCC from a primary malignant PGL/PCC. Furthermore, biopsy of PGL/PCC is contraindicated because this invasive procedure carries the risk of precipitating a hypertensive crisis, hemorrhage, and tumor cell seeding [Vanderveen et al 2009], and regardless, the pathology of the primary tumor cannot reliably predict the development of metastatic disease [Wu et al 2009].

Malignancy is defined as the presence of PGL/PCC metastases to other sites, the most common of which are bone, lung, liver, and lymph nodes. In fact, the 2017 WHO replaced the term "malignant pheochromocytoma" with "metastatic pheochromocytoma" to avoid confusion in the definition. Having to wait for evidence of metastasis to establish the malignant nature of a tumor may have introduced bias into the present understanding of the natural history of these tumors.

For PGL/PCCs that have not metastasized, operative treatment can be curative. However, once metastases have occurred there is no cure, with a five-year survival rate of 50%-69% [Hescot et al 2013, Asai et al 2017, Fishbein et al 2017, Hamidi et al 2017].

To detect metastases, the following radiographic studies can be used:

• 68-Ga-DOTATATE PET CT is a more sensitive modality to detect somatostatin receptor positive disease, especially in individuals with metastatic disease [Janssen et al 2015, Chang et al 2016, Janssen et al 2016].
• ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy is a technique that measures tumor uptake of a catecholamine analog radioisotope. MIBG has greater specificity for localization than CT and MRI, but lower sensitivity. It may be used to further characterize masses detected by CT or MRI and to look for additional sites of disease, and it is used in individuals with metastatic disease where treatment with I-131 MIBG is a consideration.
• Octreotide scintigraphy, a technique that measures tumor uptake of a somatostatin analog radioisotope, may be used in addition to MIBG scintigraphy as some MIBG-negative tumors are positive with octreotide scintigraphy. The sensitivity is fairly low, however. Octreotide scintigraphy has been largely replaced by 68-Ga-DOTATATE PET CT, where available, because of the significantly higher sensitivity.
• 2- deoxy-2-(¹⁸F)-fluoro--D-glucose position emission tomography (FDG-PET), or PET using other imaging compounds, can also assist in detecting metastatic disease.

A decisional algorithm for the use of functional imaging in hereditary PGL/PCC syndromes has recently been proposed in the Endocrine Society's Clinical Practice Guideline. See Lenders et al [2014], Figure 2 (full text).

Other tumors

• Gastrointestinal stromal tumors (GISTs). The majority of GISTs associated with PGL (Carney Stratakis syndrome; OMIM 606864) occur in individuals with a germline pathogenic variant in SDHA or SDHC. Children with GISTs are more likely to have a germline pathogenic variant in a PGL/PCC susceptibility gene than an adult with a GIST. Most GISTs associated with hereditary PGL/PCC syndromes occur in the stomach and are often multifocal (>40%).
• Pulmonary chondromas can occur together with GIST and paraganglioma (Carney triad; OMIM 604287). This is an extremely rare disorder that primarily affects young women. Adrenal cortical adenoma and esophageal leiomyoma were later shown to be associated with the syndrome [Stratakis 2009]. Carney found that 78% of affected individuals had two of the three classic tumors and 22% had all three neoplasms [Carney 1999]. Although Carney triad is most often not inherited, at least a subset of individuals (~10%) has a germline pathogenic variant in an SDHx gene [Boikos et al 2016]. In some individuals without an identified germline pathogenic variant, somatic alterations in methylation patterns of SDHx genes can be found in the GIST tumors [Boikos et al 2016].
• Renal clear cell carcinoma is part of the tumor spectrum of hereditary PCC/PGL syndromes, particularly in individuals with pathogenic variants in SDHB and SDHD [Ricketts et al 2010]. The lifetime risk of developing a renal tumor for individuals with an SDHB pathogenic variant is 4.7%, compared to 1.7% in the general population [Andrews et al 2018].
• Other tumors including papillary thyroid carcinoma, pituitary adenomas, and neuroendocrine tumors have been described in individuals with SDHx germline pathogenic variants. However, whether there is an increased risk of developing these other tumors has not been established.

Longevity. With staged tumor-targeted treatment modalities some affected individuals have lived with metastatic disease for 20 or more years [Fishbein et al 2017, Hamidi et al 2017].

Phenotype Correlations by Gene

Although persons with MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD, and TMEM127 pathogenic variants can develop pheochromocytomas and/or paragangliomas within any paraganglial tissue, the following correlations between the gene involved and tumor location are used to guide testing, surveillance, and, in some instances, recommended treatment (also see Table 2):

MAX. Germline MAX pathogenic variants have most commonly been reported in association with PCCs. Some affected individuals had additional PGLs; all those who have done so presented with PCCs initially [Comino-Méndez et al 2011, Burnichon et al 2012, Bausch et al 2017].

SDHA. Germline SDHA pathogenic variants have been identified in individuals with PCCs and PGLs (sympathetic and parasympathetic) [Burnichon et al 2010, Korpershoek et al 2011, Bausch et al 2017].

SDHAF2. Germline pathogenic variants in SDHAF2 have only been seen in association with HNPGLs [Hao et al 2009, Bayley et al 2010, Kunst et al 2011, Piccini et al 2012, Currás-Freixes et al 2015, Zhu et al 2015, Bausch et al 2017].

SDHB. Germline pathogenic variants in SDHB are generally associated with higher morbidity and mortality than pathogenic variants in the other SDHx genes [Ricketts et al 2010, Andrews et al 2018]. They are strongly associated with extra-adrenal sympathetic paragangliomas with an increased risk of metastatic disease, and, less frequently, with PCCs and parasympathetic PGLs [Andrews et al 2018]. Up to 50% of persons with metastatic extra-adrenal paragangliomas have a germline SDHB pathogenic variant [Fishbein et al 2013].

SDHC. Germline SDHC pathogenic variants appear to be primarily (but not exclusively) associated with HNPGL. However, up to 10% of SDHC-related tumors are observed in the thoracic cavity [Peczkowska et al 2008, Else et al 2014].

SDHD. SDHD pathogenic variants are mainly associated with HNPGL, although extra-adrenal PGL and PCC certainly occur [Ricketts et al 2010, Andrews et al 2018]. Persons with a germline SDHD pathogenic variant are more likely to have multifocal disease than persons with sporadic tumors or those with a germline SDHB pathogenic variant [Boedeker et al 2005].

TMEM127. Germline TMEM127 pathogenic variants are associated with adrenal PCC but can also be associated with HNPGL and extra-adrenal PGL [Neumann et al 2011]. Renal cell carcinoma has also been associated [Qin et al 2014].