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The Journal of Clinical Endocrinology and Metabolism logoLink to The Journal of Clinical Endocrinology and Metabolism
. 2009 Aug;94(8):2677–2683. doi: 10.1210/jc.2009-0496

The Approach to the Patient with Paraganglioma

Hartmut P H Neumann 1, Charis Eng 1
PMCID: PMC2730863  PMID: 19657044

Abstract

The multidisciplinary management of patients with paragangliomas and pheochromocytomas remains challenging. The cornerstone of excellent multidisciplinary management of such patients is genetic classification and management in a tertiary care referral center. Up to one third of all symptomatic presentations of pheochromocytoma or paraganglioma are due to germline mutations in one of six genes defining multiple endocrine neoplasia type 2, von Hippel-Lindau disease, neurofibromatosis type 1, and the paraganglioma syndromes types 1, 3, and 4. This genetic classification forms the basis early diagnosis and follow-up including management of relatives. Easily available clinical information such as tumor location and number, age, gender, and family history must be used to prioritize which gene should be tested. Mutation carriers should undergo regular check-up to detect and treat metachronous paraganglial and extraparaganglial tumors, and depending on syndrome, other extraparaganglial neoplasias such as medullary thyroid cancer and renal clear cell carcinomas in time. Adrenal and extraadrenal retroperitoneal tumors should be operated by surgeons highly experienced in minimal invasive, endoscopic techniques.

Multidisciplinary management of patients with paragangliomas and pheochromocytomas requires genetic classification and management in a tertiary care referral center.

A 26-yr-old male presented to an outside hospital complaining of flushing accompanied by hypertensive episodes. After 6 wk of persistent symptoms, he was diagnosed, based on a computed tomography (CT) and massive elevation of catecholamines on 24-h urine collection, with a large left adrenal mass and a second tumor in the hilus of the liver with a pheochromocytoma (Fig. 1A). 123Iodine-metaiodobenzylguanidine scintigraphy showed uptake of the adrenal mass but only marginally of the second tumor. The left adrenal was resected at open operation in 1998. The renal artery was damaged and reconstructed. Because of persistent hypertension, he had a repeat CT, which revealed complete ischemic infarction of the left kidney (Fig. 1B). At this time, the extraadrenal tumor was removed in a second operation and diagnosed as a metastasis from the adrenal pheochromocytoma. The histological report, however, contains the statement that there was no lymphatic tissue.

Figure 1.

Figure 1

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Paraganglial tumors in the reported case. A, Abdominal CT before the first operation with left adrenal pheochromocytoma. B, Abdominal CT before the second operation with extraadrenal pheochromocytoma and complete infarction of the left kidney. C, Pheochromocytoma of the right adrenal gland, detected 4 yr after first surgery. D, Left carotid body tumor operated 8 yr after first surgery.

The patient first consulted us at age 28 yr with the diagnosis of malignant pheochromocytoma. At that time, he was asymptomatic. Family history was negative for any form of paraganglial tumors and also tumors of other organs including of the central nervous system (CNS), eyes, kidneys, and pancreas. Based on 24-h urine excretion of adrenaline and noradrenaline, abdominal magnetic resonance imaging (MRI) and 123iodine-metaiodobenzylguanidine scintigraphy, he was found without evidence of tumor recurrence. Kidney function was slightly impaired (serum creatinine 1.3 mg/dl, creatinine clearance 87 ml/min per1.73 m2 body surface). In the context of the clinical picture, we re-reviewed the original histological report and came to the conclusion that the metastatic tumor could actually represent a second synchronous primary paraganglioma.

We performed genetic testing for the VHL and RET genes, both of which were mutation negative. A year later, after SDHD and SDHB were recognized as pheochromocytoma and paraganglioma susceptibility genes and genetic testing was established in our diagnostics laboratory, we identified in this patient a germline mutation in SDHD (NM_003002.2): c. 36–37 delTG. This causes a frame shift and premature stop codon downstream in the gene. Thus, the molecular diagnosis of paraganglioma syndrome type 1 (PGL 1) was made.

Subsequently we performed a 3,4-dihydroxyphenylalanine (DOPA)-positron emission tomography (PET) and an MRI of the neck. Both showed bilateral neck tumors, the larger being a left carotid body tumor (CBT). Instead of immediate surgery, the patient decided to enter a regular annual follow-up program.

Two years later, urinary noradrenaline excretion was found to be elevated, and abdominal MRI and DOPA-PET showed a 2-cm mass in the right adrenal gland (Fig. 1C). This lesion was operated using adrenal sparing endoscopic surgery with a retroperitoneal access, and histology confirmed a pheochromocytoma. Postoperative ACTH test revealed a response of the remnant adrenal cortical tissue with baseline cortisol of 56 and stimulated cortisol at 30 min of 133 and at 60 min of 136 ng/ml.

The left CBT grew slightly over the years (Fig. 1D). At age 34 yr, the patient decided to have this CBT removed, which was performed by a vascular surgeon without damage to the recurrent laryngeal nerve. The remaining head and neck paragangliomas (HNPs) did not grow over 8 yr. Currently, at age 37 yr, catecholamines remain normal.

Genetic testing was offered to the parents and the only sibling, a sister, for predictive testing. The family-specific mutation was found in the patient’s sister and his father. Both mutation carriers had three body area MRI and catecholamine excretion investigation, which all were normal.

Clinical red flags signaling heredity

Because a significant proportion of paraganglioma and pheochromocytoma are due to genetic causes, recognizing the genetic red flags (Table 1) are important for any paraganglioma/pheochromocytoma presentation. Whereas the mean age at diagnosis for pheochromocytoma and paraganglioma is 45 yr, our case presented at a young age, 26 yr. After his second operation 3 months later, another genetic red flag presented itself. He had a second primary tumor. If so, he may have had one extraadrenal pheochromocytoma, which in the scientific literature, is often termed paraganglioma.

Table 1.

Demographic, clinical, and genetic features associated with the six pheochromocytoma- and paraganglioma-associated syndromes compared with sporadic tumors

Syndrome MEN 2 VHL PGL 1 PGL 3 PGL 4 NF 1 Sporadic
Inheritance Autosomal dominant Autosomal dominant Autosomal dominant, no manifestation in offspring of mothers Autosomal dominant Autosomal dominant Autosomal dominant No
Gene name RET VHL SDHD SDHC SDHB NF1 No
Gene location 10q11.2 3p25-26 11q23 1q21 1p36 17q11.2
No. of Exons 21 3 4 6 8 57
Age at diagnosis (yr), median and range 36 (21–57) 22 (5–67) 27 (5–65) 46 (13–73) 34 (12–66) 41 (14–61) 46 (4–84)
Multifocal tumors 59% 56% 55% 9% 11% 20% 6%
Adrenal tumors 97% 92% 86% 0 43% 100% 93%
Extraadrenal abdominal tumors 3% 17% 59% 0 62% 0 8%
Thoracic tumors 0 5% 27% 0 11% 0 8%
Head and neck tumors 0 0 41% 100% 8% 0
Malignant 3% 4% 0% 0 32% 12% 4%
Family history for the given syndrome 59% 47% 18% 0 22% 16% 0
Associated tumors MTC; HPT Eye and CNS Hbl, clear cell RCC, islet cell tumors, endolymphatic sac tumors of the inner ear Rarely PTC, GIST GIST Rarely RCC, GIST Neurofibromas, café-au-lait spots, axillary freckling, optic pathway tumors, iris hamartomas
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HPT, Hyperparathyroidism; Hbl, hemangioblastoma; RCC, renal cell carcinoma; PTC, papillary thyroid carcinoma; GIST, gastrointestinal stromal tumor. Adapted from other reports (10,22,23). 

Background and terminology

The currently used terminology dates back to the 19th century and still creates confusion. Traditionally pheochromocytoma is defined as a paraganglial tumor with symptoms of vasoactivity and hormonal excess, whereas such tumors of the head and neck, which are mostly detected because of space occupation, are named glomus tumors (1,2). The sophisticated classification of the World Health Organization, whose major contributions are from pathologists, set pheochromocytoma only for adrenal medullary tumors and uses for all other locations the term paraganglioma (3,4). This schematic differentiation is lacking any additional background because pheochromocytoma means staining with chromate, a method that has been abandoned for a long time. Here, for practical reasons, paraganglioma is exclusively used for the mainly space occupying head and neck tumors, whereas pheochromocytoma is used for adrenal and extraadrenal abdominal, thoracic, and pelvic tumors. In this approach piece, we discuss all these tumors.

Pheochromocytoma-associated syndromes (Table 1)

Until recently it was believed that only 10% of pheochromocytoma and paraganglioma had a genetic basis. However, recent evidence, thanks to molecular genetic advances, points to one fourth to one third of all pheochromocytoma and paraganglioma patients harboring a gene mutation, i.e. having an inherited condition (5,6,7). To date, there are six pheochromocytoma/paraganglioma-predisposing genes.

Neurofibromatosis type 1 (NF 1) has been historically among the first described pheochromocytoma-associated syndromes with a hereditary basis. However, pheochromocytomas are found in only about 1% (range 0.1–5.7%) of NF 1 patients (8,9,10). Usually pheochromocytomas in the setting of NF 1 should not be difficult to recognize. Classical features of NF 1 include multiple neurofibromas, café-au-lait spots, and axillary freckling of the skin as well as Lisch nodules of the iris among many other lesions. The pheochromocytomas are predominantly located in the adrenals, and malignant pheochromocytoma is not infrequent. The NF1 gene is located on 17q11.2 and consists of 57 exons that encode the protein neurofibromin. There are 36 pseudogenes. In patients with NF 1 and pheochromocytoma, the mutations are spread all over the gene, and the mutation detection rate is about 90% (10). About 90% of the mutations are located in the exons, whereas 10% represent large deletions or rearrangements (9,11). Mutation analysis, however, is not indicated because patients who have pheochromocytoma and carry NF1 mutations also have neurofibromas or other signs of this syndrome (11).

Multiple endocrine neoplasia type 2 (MEN 2) is the most well-known pheochromocytoma-associated syndrome because RET gene testing in MEN 2 often forms the paradigm for the practice of clinical cancer genetics. Whereas the sine qua non of MEN 2 is medullary thyroid carcinoma (MTC) with its precursor diffuse C cell hyperplasia, about 50% of the patients have pheochromocytoma. Most MEN 2-related pheochromocytomas are benign. In MEN 2, pheochromocytomas are nearly always located in the adrenals and are often bilateral. MEN 2 is inherited as an autosomal dominant trait and is caused by germline mutations in the RET (rearranged in transfection) proto-oncogene located on 10q11.2. It encodes a receptor tyrosine kinase predominantly expressed in the neural crest and its derivatives. Because RET is a protooncogene and gain-of-function mutations activate, only limited hotspot mutations have been identified to predispose to MEN 2 (12). Thus, the great majority of germline MEN 2-causing mutations are located in codons encoding cysteines in exons 10 and 11 (12). The most fulminant and earliest onset MEN 2 subtype is MEN 2B characterized by early onset and aggressive behavior of MTC and caused by germline mutations in codons 918 and 883. Mutations in codons that predict for a very high likelihood of developing pheochromocytoma are 634 and 918. In general, patients presenting with pheochromocytoma who have MEN 2 and a RET mutation will have a personal or family history of MEN 2 features (13).

Von Hippel-Lindau syndrome (VHL) is an autosomal-dominant disorder predisposing to pheochromocytoma and other endocrine and nonendocrine neoplasias. Historically, retinal (von Hippel) and cerebellar (Lindau) hemangioblastomas predominate, the latter also occurring in the brain stem and spinal cord. Other important features of VHL are clear cell renal carcinomas, pancreatic islet cell tumors, tumors of the endolymphatic sac of the inner ear, and cystadenomas of the epididymis and broad ligament as well as multiple pancreatic or renal cysts (14). Overall, approximately 20–30% of patients with VHL display pheochromocytoma, but in certain families, the prevalence of pheochromocytoma can reach greater than 90%. Historically occurrence of pheochromocytoma is used for dividing VHL into type 1 (pheochromocytoma very rare) and type 2 (pheochromocytoma as dominant feature) (15). Type 2C is used for patients presenting only with pheochromocytoma; in long-term follow-up, however, such patients have developed retinal or CNS lesions. Recognition of pheochromocytoma as VHL associated opens important perspectives to diagnose retinal tumors before vision starts to impair and central nervous system tumors in time as well. As a rule, all tumorous components of VHL can effectively be treated if diagnosed in time.

The VHL tumor suppressor gene is located on the short arm of chromosome 3 (3p25-26) and has three exons, encoding the protein pVHL. Germline loss-of-function mutations are spread all over the gene. There are hot spots for mutations, at codons 161 and 167. A founder mutation (Y98H) was observed in about 200 subjects in the Black Forest region in Germany and in western Pennsylvania. All mutation types occur in VHL, but patients with pheochromocytoma have mostly missense mutations. Prognosis of VHL patients with missense mutations is better compared with mutations predicting a truncated protein because of more frequently occurring renal cell carcinoma (16).

The paraganglioma syndromes (PGL) have been classified by genetic analyses of families with HNPs. Numbering the syndromes type 1 to type 4 follows publication dates of the reports (17,18,19,20). Three of the four PGL predisposition genes have been identified, namely, SDHB, SDHC, and SDHD (21). The susceptibility genes encode three of the four subunits of the enzyme succinate dehydrogenase (SDH) or mitochondrial complex II, which lies at the pivotal juncture of the respiratory (electron transport) chain and the Krebs cycle (21). Complex II comprises two structural units, which anchor the enzyme (catalytic sites encoded by A and B subunits) to the mitochondrial membrane (subunits C and D). SDHB, located on 1p36, consists of eight exons and is the predisposition gene for PGL 4, SDHC (located on 1q36, 6 exons) for PGL 3, and SDHD (located on 11q23, 4 exons) to PGL 1 (Table 1). The gene for PGL 2, mapped to 11q13, has not yet been identified. Mutations of SDHA do not predispose to development of paraganglioma tumors but homozygous or compound heterozygous mutations cause Leigh syndrome. The most prevalent among these syndromes is PGL 1, caused by germline SDHD mutations, followed by PGL 4 (SDHB), whereas PGL 3 (SDHC) is rare. The spectrum of manifestations of PGL 1, PGL 3, and PGL 4 shows differences but also overlap. Adrenal, extraadrenal abdominal, and thoracic pheochromocytomas are components of PGL 1 and PGL 4 but very rarely of PGL 3 (6,7,22,23,24,25). Patients with PGL 1 (SDHD mutation carriers) nearly always display benign and multiple adrenal pheochromocytomas and HNPs (7,22). Patients with PGL 4 (SDHB mutation carriers) often display extraadrenal or thoracic or HNPs (7,22). About one third of the patients have metastases. Patients with PGL 3 (SDHC mutation carriers) have characteristics of age, manifestation, and tumor number similar to those with sporadic HNPs (23).

Transmission of PGL 3 and PGL 4 is autosomal dominant. In contrast, PGL 1 is autosomal dominant with parent of origin effect. So far, histologically proven tumors in a mother and an offspring have not been reported (26,27).

In a small number of patients with familial pheochromocytoma, a mutation has not yet been identified. Therefore, probably other susceptibility genes for autosomal dominant pheochromocytoma exist (28).

Identifying germline mutations in pheochromocytoma and paraganglioma patients

Hereditary pheochromocytoma and paraganglioma syndromes should be recognized as early as possible. Identification of a patient as a carrier of a germline mutation opens avenues for better understanding of etiology, i.e. a molecular diagnosis, gene-specific medical management, and follow-up. Of equal importance is the ability for predictive testing of as-yet-unaffected relatives such that mutation-carrying relatives can undergo a surveillance program. All these aspects together form the field of molecular genetics-based preventive medicine.

Guidelines for genetic screening in patients with pheochromocytoma or paraganglioma

A step-by-step approach should be used to start molecular genetic testing with the best candidate gene (Table 2). This procedure is time and cost saving. Algorithms for which gene should be selected to prioritize testing have been suggested by several groups (13,29,30,31,32). A common weakness of these suggested algorithms is, according to the rarely occurring paraganglial tumors, the small sample sizes of subsets like extraadrenal or malignant pheochromocytoma, which does not allow more accurate statistic analyses.

Table 2.

Work-up of all pheochromocytoma/paraganglioma patients before initiating genetic testing

1. Information to be asked from the patient and the primary provider
Age at diagnosis, gender
Tumor location
Tumor number
Previous operations for pheochromocytoma or HNP as well as tumors of the eye, CNS, kidney, thyroid, pancreas
Family history for pheochromocytoma or HNP as well as tumors of the eye, CNS, kidney, thyroid, pancreas
Place of living (endemic areas of founder mutations)
2. Information to be checked by the primary provider
MRI and CT of the abdomen: tumors of the kidney or pancreas
Calcitonin
3. Information from the pathologist on SDHB immunohostochemistry
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Family history for paraganglial tumors, multiple tumors, and young age at diagnosis are associated with a high probability of finding a germline mutation. All individuals with malignant pheochromocytoma should be genetically tested because the prognosis in carriers of SDHB mutations is worse compared with non-SDHB-positive ones (33,34). The major challenge is the patient with a single adrenal pheochromocytoma and no family history. In addition, a clear cutoff for age at diagnosis remains to be defined.

For HNPs, in a consortial approach with large sample size, we have used the multiple logistic regression analyses to identify predictors of whether to gene test and, if so, which gene to prioritize based on routinely available demographic and clinical parameters. Family history, multiple tumors, male gender, malignant tumors, and age 40 yr or younger are predictors for inherited HNP, and nearly exclusively, SDHB, SDHC, and SDHD are affected (35). Mutations of the VHL and RET genes are extremely rare; most of these latter patients had typical clinical manifestations or a family history for MEN 2 or VHL (35). HNP in NF 1 is even less frequent. Therefore, mutation analysis of VHL, RET, and NF1 should not be performed unless there is clear clinical evidence of these syndromic features in the patient and/or family.

Recently a different approach to identify paraganglial tumors associated with mutations of the genes SDHB, SDHC, and SDHD (SDHx) has been presented by a Dutch group. They used tumor tissue and performed immunohistochemistry against SDH, in particular anti-SDHB (36,37). Normal staining was found only in patients without mutations in an SDHx gene. This elegant potentially promising approach must be tested and validated in large series before giving general recommendations on this procedure.

Prediction for presence of a germline mutation in our case

Our case presented at age 26 yr and had multifocal pheochromocytoma with one tumor in the left adrenal and another in the retroperitoneum. Originally considered malignant, the diagnosis of the retroperitoneal mass was revised to a second primary tumor based on histological re-review. This is also supported by the SDHD mutation because such carriers very rarely have malignant paraganglial tumors. Remarkably he was without a family history indicating any pheochromocytoma-associated syndrome.

It is very important to emphasize that this type of easily accessed demographic and clinical information (Tables 1 and 2) is instrumental for this patient for molecular classification, which dictates management for the patient as well as his/her family. Thus, the most likely genes in our case given his age, multifocal and extraadrenal pheochromocytoma would be SDHD.

Back to the case: from molecular classification to the approach

A patient identified with a germline mutation should be managed in an experienced center. This is vital for multidisciplinary gene-based preventive medicine in general.

As the first and major important part, the patient needs to be investigated for additional lesions of the given syndrome. Because most of these subjects are young and in the work force, the visit at the center must be well prepared and should be completed within 1 d. For RET mutation carriers, a pentagastrin test and PTH measurement will provide with evidence of medullary thyroid cancer or hyperparathyroidism to perform thyroidectomy before metastases have settled. In carriers of VHL mutations, ophthalmoscopy and MRI of the brain and spinal cord will detect hemangioblastomas and provide with treatment options to prevent blindness or neurological problems. A re-review of abdominal imaging performed during the diagnosis of pheochromocytoma will confirm absence of renal cancer, pancreatic cysts, or islet cell tumor, the typical visceral manifestations of VHL. In carriers of mutations of the SDHB, SDHC, and SDHD genes, a serial imaging of the complete autonomic nervous system using MRI of the skull base, thorax, and abdomen including the pelvis should be done.

Once the initial multidisciplinary assessment is complete, the second part entails planning of regular follow-up. Investigation program and intervals vary from syndrome to syndrome. Yearly check-ups are mostly recommended. Individual counseling, however, is important and can be based on risk profiles likewise low recurrence frequency of paraganglial tumors in carriers of SDHC mutations or adjusted to the individual mutation (25,38).

The benefit from a work-up in such a preventive medicine center is illustrated by our case. He developed a pheochromocytoma in the contralateral adrenal after 2 yr and had successful removal by retroperitoneal endoscopic adrenal sparing surgery. Again, 4 yr later, when growth of a carotid body tumor was seen, he had removal of this paraganglioma without side effects.

The approach to the relatives

Finding a germline mutation in the patient allows for predictive testing of as-yet-unaffected members of his family in the setting of genetic counseling in an experienced center. This is the third important service of a prevention medicine center in the given context. It is a unique option because this is an outstanding chance to cure patients from potentially malignant tumors, if diagnosed, which mainly reflects renal cell cancer in VHL and medullary thyroid cancer in MEN 2.

In our report, the case’s father and sister were found to carry the mutation as well. Because manifestation of neoplasias due to SDHD mutation has a transmitting parent-of-origin effect, the father may have inherited the mutation from his mother, in which case he will never develop pheochromocytoma or PGL. Identification of the sister as a mutation carrier here allows her to undergo regular surveillance with total body imaging (CT/MRI).

The approach to the diagnosis malignant pheochromocytoma

The clinical call of malignancy remains a challenge. When pheochromocytoma and paraganganglioma occur in extraparaganglial sites such as within the liver parenchyma or in the bone, it is considered malignant. Although lymph node metastases occur, tumors occurring at sites of paraganglia should be considered to be extraadrenal pheochromocytoma before classified as metastases. As illustrated by our case, the second tumor was believed to be a metastasis, presumably lymphatic, but without histological evidence of lymph node tissue, and because of its location, this was more accurately a second primary. Furthermore, germline SDHD mutation carriers should be especially reconsidered in this aspect because malignant pheochromocytoma and paraganglioma are very rare in PGL 1. In contrast, those with SDHB mutations have a significant likelihood of malignancy.

The approach to pheochromocytoma by the surgeon

Finally, the treatment options for pheochromocytomas need to be discussed. Starting with the given case, many patients would have had the second adrenal removed. These patients, however, would have a life-long dependency from steroid replacement, which also must be balanced against the risk for further pheochromocytoma and potentially even malignant pheochromocytoma. In our extended experience, the relapse and malignancy risks are low (39,40). A second challenge was the status after two open surgeries, one with a major complication. The fortunate technical advance for our case was retroperitoneal endoscopic adrenal-sparing removal of the pheochromocytoma. Postoperatively he was not depending on steroid medication.

The general recommendation is that all patients with pheochromocytoma, including those of extraadrenal abdominal, pelvic, and thoracic sites and regardless of their size, can and should be operated endoscopically. This provocative statement is still open to debate, and many surgeons continue to perform open surgeries up to now. Again, endoscopic/minimally invasive surgery should be performed in major medical centers. Given the rarity of pheochromocytomas, the value of cumulative know-how becomes self-evident. Probably the broadest experience worldwide represents the series of 126 cases in Essen/Germany (41). In this center for the last 14 yr, all pheochromocytomas have been endoscopically removed. As a guideline, hospital stay, blood loss, intraoperative complications, and recovery as well as the cosmetic results are equal or superior to conventional open surgery. Adrenal-sparing surgery is routine under the demand for rapid removal of the potential complications of the tumor. Multifocal, including extraadrenal, tumors have always been removed in a single session, even with tumor size up to 12 cm in diameter (41). Regarding the preoperative work-up, MRI or CT staging and α-blockade are standard, but it is controversial whether pheochromocytoma patients should also have preoperative MIBG or DOPA-PET. Preoperative DOPA-PET or dopamine-PET scanning would almost certainly have detected our case’s second tumor (42,43).

Footnotes

This work was supported by Grants 107995 from the Deutsche Krebshilfe (to H.P.H.N.), NE 571/5-3 from the Deutsche Forschungsgemeinschaft (to H.P.H.N.), and LSHC-CT-2005-518200 from the European Union (to H.P.H.N.). C.E. is the recipient of a Doris Duke Distinguished Clinical Scientist Award and is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic and National Institutes of Health-funded investigator.

Disclosure Summary: H.P.H.N. and C.E. have nothing to disclose.

Abbreviations: CBT, Carotid body tumor; CNS, central nervous system; CT, computed tomography; DOPA, 3,4-dihydroxyphenylalanine; HNP, head and neck paraganglioma; MEN 2, multiple endocrine neoplasia type 2; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; NF 1, neurofibromatosis type 1; PET, positron emission tomography; PGL, paraganglioma syndrome; PGL 1, paraganglioma syndrome type 1; SDH, succinate dehydrogenase; VHL, Von Hippel-Lindau syndrome.

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