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Pheochromocytomas and Paragangliomas: An Update on Recent Molecular Genetic Advances and Criteria for Malignancy

Guo, Zhenying MD*,†; Lloyd, Ricardo V. MD, PhD*

doi: 10.1097/PAP.0000000000000086
Review Articles

Pheochromocytomas are uncommon neuroendocrine tumors arising in the adrenal medulla, whereas paragangliomas arise from chromaffin cells in sympathetic and parasympathetic locations outside of the adrenal gland. Molecular genetic studies in the past few years have identified >10 genes involved in the pathogenesis of pheochromocytomas and paragangliomas, including RET oncogene, involved in the pathogenesis of multiple endocrine neoplasia (MEN) 2A and 2B, von Hippel-Lindau tumor-suppressor gene, neurofibromatosis type 1 gene, succinate dehydrogenase, THEM127, and several others. The presence of genetic alterations in some of these genes such as in MEN 2A and 2B can be used to diagnose these disorders clinically, and other mutations such as succinate dehydrogenase can be used in the pathologic prediction of benign and malignant pheochromocytomas and paragangliomas. Although it has been difficult to separate benign and malignant pheochromocytomas and paragangliomas, recent studies that may predict the behavior of these chromaffin-derived neoplasms have been reported. The Pheochromocytoma of the Adrenal Scale Score and the Grading system for Adrenal Pheochromocytoma and Paraganglioma scoring system are also discussed.

*University of Wisconsin School of Medicine and Public Health, Madison, WI

Zhejiang Cancer Hospital, Hangzhou, China

The authors have no funding or conflicts of interest to disclose.

Reprints: Ricardo V. Lloyd, MD, PhD, Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792 (e-mail:

Pheochromocytoma and paraganglioma are uncommon neuroendocrine tumors. Pheochromocytomas arise in the adrenal medulla and are derived from chromaffin cells of neural crest origin (Figs. 1A–E). Extra-adrenal pheochromocytomas or paragangliomas (Fig. 1F) arise from chromaffin cells in sympathoadrenal and parasympathetic paraganglia.1 Pheochromocytomas and paragangliomas are very similar histologically. They generally secrete catecholamines, mainly norepinephrine, but pheochromocytomas may also secrete epinephrine. Head and neck paragangliomas, however, rarely produce significant amounts of catecholamines. Serious morbidity and mortality associated with these tumors are related to the potent effects of catecholamines on various organs, especially those of the cardiovascular system. Their prevalence has been estimated to lie between 1:6500 and 1:2500 in the United States.2 The annual incidence in the United States ranges from 500 to 1600 cases per year. Autopsy series have revealed a higher prevalence of about 1:2000, suggesting that many tumors remain unrecognized and are diagnosed only during postmortem examination.3 Misdiagnoses of pheochromocytomas and insufficient preoperative preparation increase the patient’s risk of intraoperative complications.4



Pheochromocytomas and paragangliomas are the most commonly inherited neuroendocrine tumors. Hereditary forms were once thought to represent around 10% of all pheochromocytomas and paragangliomas, but Neumann et al5 reported germline mutations involving 4 known susceptibility genes in 24% of patients with clinical findings suggestive of sporadic tumors. Mannelli and colleagues reported that germline mutations were detected in up to 32.1% of cases, but the frequency varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history.6,7 It is estimated that in children the prevalence may be as high as 40%.8–10 This review focuses on recent developments in genetic advances of pheochromocytomas and paragangliomas and in the histopathologic diagnosis of malignancy in these uncommon neuroendocrine tumors.

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In recent years, significant progress has been made in understanding the genetic changes of pheochromocytomas and paragangliomas. Approximately 10 more genes have been discovered including RET, a tyrosine kinase, von Hippel-Lindau (VHL) tumor-suppressor gene, neurofibromatosis type 1 (NF type 1), succinate dehydrogenase (SDHA, SDHB, SDHC, SDHD, and SDHAF2), TMEM127, Myc-associated factor X (MAX), KIF1B, H-RAS, HIF2, PHD2, and FH.11 Two distinct gene clusters involved in the tumorigenesis of pheochromocytomas/paragangliomas according to their transcriptional profile include a kinase receptor–signaling gene cluster (associated with RET/NF1/TMEM127/MAX/KIF1B mutations) and a pseudo-hypoxic gene cluster (associated with mutations in VHL/SDHx/PHD2 genes).12

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Multiple Endocrine Neoplasia and RET Gene

Multiple endocrine neoplasia (MEN 2) is an autosomal dominant disorder characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism. This disease is caused by various mutations in the RET proto-oncogene, a transmembrane tyrosine kinase. The activating mutations have been well delineated, and lead to constitutive activation of the protein and subsequent unregulated cell growth. Depending on the most frequent manifestations, there are 3 subtypes of MEN associated with RET mutations: MEN 2A, MEN 2B, and familial MTC. MEN 2A is the most frequent subtype representing around 75% of MEN 2 cases.13 The most common mutations in MEN 2A are within the cysteine-rich extracellular tyrosine kinase receptor, at codons 634 in exon 11, and codons 620, 618, 611, 609 in exon 10. A codon 634 mutation is present in nearly 90% of patients with MEN 2A who develop pheochromocytomas.14,15 Subgroup analysis of patients with RET 634 mutations with and without pheochromocytomas showed that this disorder was not associated with a more advanced stage of MTC at diagnosis or with a shorter survival.16 Therefore, the presence of such a mutation should heighten surveillance for the development of pheochromocytomas in patients with MEN 2B who have been found to have a germline mutation in RET, either M918T (>95%) or A883F (>3.6%).17,18

MEN2 can also be found in individuals without a family history who develop de novo mutations (eg, 15% of MEN 2A, >50% of MEN 2B, and 10% of familial MTC). Symptoms and signs of catecholamine hypersecretion should be considered. Pheochromocytomas occur most often during young adult to mid-adult life. MEN2-related pheochromocytomas are characterized by increased plasma metanephrine. In all cases of pheochromocytomas, assessment of serum calcitonin, calcium, and parathyroid hormone is recommended as pheochromocytomas may be the first clinical manifestation of MEN 2. Elevated levels of serum calcitonin would strongly suggest a diagnosis of MTC. Pheochromocytomas in MEN 2 are usually benign but have a higher chance for recurrence. The pheochromocytomas found in both MEN syndromes are typically of adrenal origin and are bilateral in about 50% of cases. It is very rare to develop extra-adrenal disease.

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Von Hippel-Lindau Type 2 and Von Hippel-Lindau Tumor-suppressor Gene

Von Hippel-Lindau (VHL) disease is a hereditary, autosomal dominant syndrome associated with various benign and malignant tumors.19 A constellation of clinical presentations of VHL disease have been reported, including retinal angioma, hemangioblastoma of the central nervous system, pheochromocytoma, renal cell carcinoma, and epididymal cystadenoma.20 Cysts are usually associated with the tumors. On the basis of clinical manifestations, patients with VHL are classified into VHL type 1 (without pheochromocytomas) and VHL type 2 (with pheochromocytomas). VHL type 2 is further divided into 3 subcategories: type 2A, type 2B, and type 2C. VHL type 2A includes pheochromocytoma with other hemangioblastomas in the central nervous system, but without renal cell carcinomas. Type 2B patients present with pheochromocytoma, renal cell carcinomas and the central nervous system tumors. Type 2C disease presents only with pheochromocytomas, without other manifestations of the disease. It is noteworthy that only a few mutations for VHL type 2C have been identified.21 Latif and colleagues performed positional cloning for the disease with the accumulation of DNA in VHL families, and the VHL gene was identified in 1993. This gene was designated as the VHL tumor-suppressor gene, and is located on chromosome 3p25-26. It comprises 3 exons that encode for the 2 isoforms of the VHL protein (pVHL).22

VHL type 2 families almost invariably present with VHL missense mutations. Particularly, missense mutations at codon 167 were associated with a high risk of developing pheochromocytomas. VHL mutations associated with the phenotype 2A or 2B have been shown to affect the proteasomal degradation of HIF1, whereas type 2C mutations do not disrupt the ability of pVHL to downregulate HIF1, suggesting that pheochromocytoma formation is not related with HIF1 expression levels.23,24 There are probably other molecular mechanisms involved in pheochromocytoma development. It has been proposed that VHL-associated pheochromocytoma tumorigenesis is associated with abnormal extracellular matrix formation and to upregulation of tyrosine hydroxylase, leading to increased catecholamine synthesis.25,26 Transcription of the tyrosine hydroxylase (gene, which encodes the final and rate-limiting enzyme in catecholamine synthesis) is hypoxia inducible and seems to be regulated by VHL protein.25,26 Moreover, VHL type 2C patients seem to be incapable of binding and regulating the assembly of fibronectin.23,24 This indicates that abnormal extracellular matrix formation may play a role in the pathogenesis of pheochromocytomas. The VHL gene promoter in pheochromocytomas has been shown to have increased methylation compared with normal adrenal.27

The incidence of pheochromocytomas in VHL type 2 is 10% to 20%, and the mean age at presentation is 30, which is about 10 years younger than in patients with sporadic pheochromocytomas.28 Pheochromocytomas associated with VHL type 2 are usually intra-adrenal (88%), and up to 50% are bilateral. As with most familial endocrine disorders, these patients have an increased risk for having multiple tumors, but they have a low likelihood of malignant transformation.

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Neurofibromatosis Type 1

Neurofibromatosis (NF) type 1, or Von Recklinghausen disease, is an autosomal dominant disorder.29 Patients with NF type 1 are at higher risk than the general population of developing various tumors including peripheral nerve sheath tumors, gastrointestinal stromal tumors (GISTs), rhabdomyosarcoma, breast cancer, and pheochromocytomas.30 NF type 1 is caused by loss of function mutations in tumor-suppressor gene NF1,31 which is located on chromosome 17q11.2. The gene has 60 exons that encode for neurofibromin, a negative regulator of RAS proteins. Neurofibromin is a GTPase-activating protein that promotes the conversion of active RAS-GTP to its inactive form, RAS-GDP. Mutations in NF1 gene result in constitutive activation of RAS triggering a kinase cascade and the activation of the mitogen-activated protein kinases (MAPK), mammalian target of rapamycin (mTOR), and PI3K pathways, regulating the transcription of genes associated with cell proliferation, cell death, differentiation, and migration.32 NF1 loss of function is a frequent event in the tumorigenesis of sporadic pheochromocytoma.33 It is of interest that the NF1 gene has recently been shown to carry somatic, inactivating mutations in a significant number of sporadic pheochromocytomas in 2 independent studies.33,34 A majority of the tumors displayed loss of heterozygosity (LOH) at the NF1 locus and a low NF1 mRNA expression. In view of previous findings that many sporadic pheochromocytomas cluster with NF type 1–related pheochromocytomas instead of forming clusters of their own, NF1 inactivation appears to be an important step in the pathogenesis of a large number of sporadic pheochromocytomas. Somatic NF1 inactivation is a frequent event in sporadic pheochromocytomas.34 Composite tumors with neuroblastoma, ganglioneuroma, or ganglioneuroblastoma may be associated with neurofibromatosis.35

Pheochromocytomas are uncommon in NF type 1, affecting approximately 0.1% to 6% of patients. A prevalence rate as high as 13% has been reported in autopsy series, suggesting that the diagnosis of pheochromocytomas may be missed in some NF type 1 patients. The mean age at presentation of pheochromocytomas is 42 years. The majority of patients have unilateral adrenal tumors, whereas 10% of patients present with bilateral tumors and 6% have abdominal tumors. Malignant pheochromocytomas were reported in 12% of NF type 1 patients.36 Similarly to MEN 2–related pheochromocytomas, in NF type 1 these tumors have been shown to produce norepinephrine and less commonly epinephrine, resulting in increased levels of metanephrine. Although NF type 1–related pheochromocytomas are rare, because of the risk of malignancy, it has been proposed that any patient with hypertension/paroxysmal hypertension or with symptoms of excess catecholamine, such as headache, sweating, palpitations, or anxiety, should undergo 24-hour urine or plasma metanephrine measurement. Unlike mutations in VHL or MEN 2 disorders, NF type 1 mutations that offer an increased risk in pheochromocytoma remain to be identified. A study carried out by Bausch and colleagues in NF type 1 patients with pheochromocytomas showed that the cysteine-serine–rich domain was affected in about a third of the cases, whereas the Ras GTPase–activating protein domain was affected in about 10% of cases, suggesting that the cysteine-serine–rich domain could play a role in the formation of NF1-associated pheochromocytomas. Moreover, in accordance with the Knudson 2-hit theory that states that pheochromocytoma development requires biallelic inactivation, LOH was shown in NF type 1–related pheochromocytomas. No association was found between NF1 mutational genotype and the clinical features of pheochromocytomas.37 NF1 patients were reported to have significantly smaller tumors and less hypertension than other patients with pheochromocytoma, perhaps due to higher frequency of imaging occasioned by other neoplasms that they may have. The common recommendation to screen for pheochromocytoma when hypertension develops would have failed to initiate screening in 83% of these NF1 patients. Some authors have suggested that routine screening for pheochromocytoma in all NF1 patients may be warranted.38

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Other Pheochromocytoma Susceptibility Genes


TMEM127 is a tumor-suppressor gene initially identified as a pheochromocytoma susceptibility gene and later reported to be associated with the development of paragangliomas of the head and neck and abdomen.39–41 The TMEM127 gene encodes a highly conserved transmembrane protein, transmembrane protein 127, which is associated with several cellular organelles and is thought to limit mTORC1 activation thus controlling protein synthesis and cell survival. Mutations in this gene are inherited in an autosomal dominant manner and induce tumor development by enhancing the kinase-dependent signaling pathways, similarly to mutated RET and NF1 genes.42 Patients may present with either unilateral or bilateral pheochromocytomas. The mean age at diagnosis is around 42 years and the risk of malignancy is very low (≈1%). The prevalence of TMEM127 mutations in patients with pheochromocytomas and paragangliomas varies between 0.9 and 2%. Different missense, frameshift, or nonsenseTMEM127 mutations have been found across the 3 exons of the gene.43,44

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MAX gene mutations were first identified as responsible for the development of bilateral pheochromocytomas in 8 index patients.45 This association was further confirmed by another study of 1694 patients with pheochromocytomas and paragangliomas.46 The latter study documented that 68% of MAX germline mutation patients presented with bilateral or multifocal pheochromocytoma and that 16% developed additional thoracoabdominal paragangliomas. Overall, MAX germline mutations were found in 1.12% of patients without other mutations. Both studies presented patients with metastatic disease, but whether the risk of malignancy is associated with MAX mutations needs to be further examined. MAX encodes for MAX protein, which is a component of the MYC-MAX-MXD1 complex that regulates cell proliferation, differentiation, and apoptosis.47 Mutations have a paternal mode of transmission and result in the loss of the wild-type allele with consequent abrogation of protein expression. Consequently, inhibition of MYC-dependent cell transformation by MAX protein is disrupted, leading to tumor development. MAX tumors produce predominantly normetanephrine.48

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Somatic mutations in H-RAS gene was identified in 4 male patients presenting with pheochromocytomas (3 patients) and paraganglioma (1 patient).49 A recent study described an additional H-RAS somatic mutation in a patient with unilateral pheochromocytoma.50

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The Kinesin family member 1B (KIF1B) was found to be associated with missense mutations related to pheochromocytomas in 2 cases.51 KIF1B has 2 protein isoforms, KIF1Bα and KIF1Bβ. KIF1Bβ acts downstream from PHD3 to induce apoptosis. Loss of function mutations in KIF1Bβ could protect neuroblasts from apoptosis, leading to tumor development.52 Transcriptional analysis of KIF1Bβ mutations in pheochromocytomas showed that these tumors are transcriptionally related to RET and NF1-associated tumors.

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Immunohistochemical Features as Markers of Malignancy in Pheochromocytoma

Many immunohistochemical (IHC) markers of malignancy in pheochromocytomas and paragangliomas have been reported. Chromogranin A (CgA), a major constituent of the matrix of catecholamine-containing secretory granules, can distinguish pheochromocytomas and paragangliomas from nonendocrine tumors including tumors of the adrenal cortex (Fig. 1D).53

Distinction of pheochromocytomas and paragangliomas from other neuroendocrine tumors that also express CgA is challenging especially with small biopsy specimens. Panels of antibodies, including S100 protein, as well as tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis, and exclusion of staining for cytokeratin may be useful. An exception to lack of cytokeratin staining is the paragangliomas that are present in the sacral region. Sustentacular cells are S100 positive.54,55 A difference observed between benign and malignant pheochromocytomas with expression of different portions of the CgA molecule has been reported, but more studies are needed to validate these findings.56,57

Recently, intense IGF-1R labeling was reported in cases of pheochromocytomas and paragangliomas with confirmed metastatic disease. The risk of metastases was much higher in tumors with IGF-1R labeling.58 HIF1α was reported as a discriminatory biomarker for the presence of metastatic disease. Lack of vascular invasion, tumor necrosis, and low HIF1α expression identified tumors with a lower risk of malignancy. Strong membranous CaIX expression as a potential marker for VHL disease in patients presenting with pheochromocytomas has been reported.59 Xu et al60 noted that malignant pheochromocytomas overexpressed HSP90 and STAT3, and the combination of HSP90 and STAT3 might be useful to separate malignant from benign pheochromocytomas.

Stathmin has been reported to be more highly expressed in pheochromocytomas compared with the normal adrenal glands. There was higher expression of stathmin in malignant pheochromocytomas compared with pheochromocytomas without metastasis. Stathmin was present in a wide variety of endocrine tumors and was most highly expressed in rapidly proliferating tumors including anaplastic thyroid carcinomas, Merkel cell carcinomas of the skin, and small cell carcinomas of the lung. These results show that stathmin is expressed at higher levels in more rapidly proliferating endocrine tumors. However, stathmin is probably not useful as a stand-alone marker to determine malignancy for individual tumors.61

For the general surgical pathologist the use of chromogranin, synaptophysin, and S100 protein is usually sufficient to support the diagnosis of a pheochromocytoma. Additional IHC markers and molecular markers should be used in large specialized centers.

Ki-67 is a useful marker of proliferations in many malignancies. It has been shown to correlate with malignancy in a number of studies of pheochromocytomas.62,63 A Ki-67 index of 3% or higher is considered to be a useful parameter in predicting malignant potential (Fig. 1E) because benign pheochromocytomas have been shown to have indices of <3%. However, despite a high specificity for malignancy, Ki-67 index lacks sensitivity in establishing a diagnosis of malignancy.64,65 The use of Ki-67 in a new system for grading pheochromocytomas and paragangliomas will be discussed later in this review.

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MicroRNAs are short fragments of noncoding RNAs between 17 and 24 nucleotides in length. Some microRNAs have been shown to function as oncogenes or tumor-suppressor genes. MicroRNA(miR)-139-3p, miR-541, and miR-765 were significantly differentially expressed between sporadic benign and VHL-related pheochromocytomas. Significantly higher expression of miR-885-5p and miR-1225-3p was found in MEN 2 and sporadic recurring pheochromocytomas, respectively. MiR-1225-3p has been reported to be useful for identifying recurring pheochromocytomas.66 However, no marker has emerged that can be translated into routine clinical practice at this time.

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Prognosis of Pheochromocytoma

The classic triad of symptoms including headaches, excessive perspiration, and palpitations has been historically associated with pheochromocytomas. The majority of pheochromocytomas are benign. Historically, the classification of pheochromocytomas and paragangliomas as malignant has been based on metastatic disease rather than on histologic criteria. Malignancy is reported in up to 13% of pheochromocytomas.1 The prognosis for malignant pheochromocytomas and paragangliomas is poor, with a 5-year mortality rate of >50%.67 There is currently no effective or curative treatment, but surgery, chemotherapy, and radiotherapy are beneficial in some patients.

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Paragangliomas are neuroendocrine tumors that arise in the extra-adrenal sympathetic and parasympathetic paraganglia. They secrete less norepinephrine than pheochromocytomas and are classified as sympathetic or parasympathetic depending on the type of paraganglia from which they arise. Sympathetic paragangliomas arise from chromaffin cells of paraganglia along the sympathetic chains and are usually located in the chest, abdomen, or pelvis. Parasympathetic paragangliomas arise from the glomera that are distributed along parasympathetic nerves in the head, neck, and upper mediastinum.

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SDH Mutation

Familial paraganglioma syndromes are a group of autosomal dominant disorders responsible for the development of paragangliomas and pheochromocytomas caused by mutations in the genes encoding the SDH mitochondrial complex. SDH or respiratory complex II is an enzyme complex that catalyzes the oxidation of succinate to fumarate in the Krebs cycle and participates in the electron transport chain.64 SDH is composed of 4 subunits encoded by the corresponding genes: SDHA, SDHB, SDHC, and SDHD. Complex subunits A (flavoprotein) and B (iron-sulfur protein) constitute the catalytic core of the enzyme, whereas subunits C and D anchor the complex to the inner mitochondrial membrane. In general, inactivating mutations in one of the SDHx genes leads to accumulation of succinate and formation of reactive oxygen species, stabilizing HIFα and activating hypoxia-dependent pathways.68

SDHA mutations, initially described in autosomal recessively inherited juvenile encephalopathy,69 were thought to be absent from patients with pheochromocytomas/paragangliomas. However, recent reports implicate germline mutations of SDHA in pheochromocytomas/paragangliomas.70 SDH complex assembly factor 2 (SDHAF2) encodes an evolutionarily highly conserved flavin-adenine dinucleotide factor71 and is involved in the flavination of SDHA. A missense mutation in the conserved region of SDHAF2 is associated with head and neck paragangliomas.72,73 The few SDHA-affected individuals described so far have presented with distinct phenotypic characteristics: pheochromocytomas that include sympathetic (abdominal and thoracic) and parasympathetic head and neck paragangliomas Missense and nonsense mutations have been reported without any genotype-phenotype correlations.74–76 Recently, SDHA gene mutations have also been implicated in the development of GISTs.77,78

SDHB mutations were initially described by Gimenez-Roqueplo et al.79 It has been reported that extra-adrenal site, recurrence, and malignancy were strongly associated with SDHB mutations and suggested that the presence of SDHB mutants should be considered a high-risk factor for malignancy or recurrence.80 A malignant paraganglioma was documented in 37.5% of SDHB carriers, 3.1% of SDHD carriers, and none of the SDHC mutation carriers.7 SDHB mutations are present in approximately 1.7% to 6.7% of patients with apparently sporadic pheochromocytomas. Although initially thought to have a high clinical penetrance, increased testing of these cases indicates a penetrance of 25% to 40%.81 SDHB mutations exhibit the highest frequency of malignancy. Approximately 20% of mutation carriers will develop malignant disease, and up to 50% of patients with malignant pheochromocytomas and paragangliomas harbored a germline SDHB mutation.82–85 In addition to pheochromocytomas and paragangliomas, SDHB mutations are also associated with renal cell carcinoma, which can have an aggressive phenotype in young patients.86,87 It has been recommended that patients with SDHB mutations be offered surveillance screening for renal cell carcinoma.88 American Society of Clinical Oncology guidelines suggesting that genetic testing should be performed if the risk of a hereditable mutation is at least 10% or if it will affect medical management. This suggests that patients with pheochromocytomas and paragangliomas should probably undergo clinical genetic testing.89

SDHD mutation is associated with head and neck paragangliomas.90 As with other familial paragangliomas, these patients are more likely to have multifocal disease. Both SDHB-related and SDHD-related pheochromocytomas and paragangliomas typically secrete norepinephrine and dopamine, or dopamine alone. Neumann et al82 have shown that among 34 patients with mutations in the SDHD gene, 79% had head and neck paragangliomas, 53% had pheochromocytomas, and 39% thoracic/abdominal paragangliomas, whereas 74% of the patients presented with multiple tumors. Mean age at presentation is around 30 years.91 Ricketts et al86 estimated the risk of developing head and neck paragangliomas at 71% and the risk of pheochromocytoma at 29%, at age 60 in these patients. Malignancy has rarely been found in SDHD-derived sympathetic or parasympathetic paragangliomas.92,93 Several different mutations have been described in exons 2 to 4 of SDHD, mainly nonsense, missense, and frameshift mutations, but its relation with the phenotypic expression of the disease is still unclear.

SDHC gene mutations are rare. They are associated with benign head and neck paragangliomas, although a case of extra-adrenal abdominal pheochromocytoma has been reported.94 SDHC mutations were initially described in head and neck paragangliomas, but have since been reported in adrenal pheochromocytomas and paragangliomas at other sites.7 The delineation of specific SDH subunit mutations has led to an improved understanding of disease associations. Pheochromocytomas and paragangliomas can be found in association with GISTs and pulmonary chondromas in the Carney triad, whereas SDHB and SDHC mutations are present in approximately 12% of patients with GISTs without PDGFRA receptor mutations.95,96

Recently, the relationship between the activity of respiratory chain enzyme complex II, ATP/ADP/AMP content, and catecholamine content in paraganglioma tumors with an SDHx mutation was established for the first time.97

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HIF2A and PHD2

Two somatic mutations in the hypoxia-inducible factor 2α (HIF2A) gene in 2 patients with polycythemia and multiple paragangliomas have been described.98 Both mutations affected pVHL hydroxylation, impairing HIF2A degradation leading to an intact/increased transcriptional activity of genes downstream of HIF2A, such as VEGFA and erythropoietin.98 These findings were further confirmed by recent observations that somatic HIF2A mutations probably caused the development of polycythemia,99,100 multiple pheochromocytomas/paragangliomas, and somatostatinomas.101,102 Somatic mutations in HIF2A have also been identified in sporadic pheochromocytomas/paragangliomas in the absence of erythrocytosis.103 The occurrence of multiple tumors presenting with the same somatic mutations without a familial history suggests that there may be a de novo postzygotic event early in embryogenesis.104 The prolyl hydroxylase domain (PHD) family is responsible for hydroxylation of prolyl residues of HIFα under normoxic conditions, allowing the pVHL binding and proteosomal degradation of HIFα proteins.105 Ladroue et al106 reported on a patient presenting with erythrocytosis and recurrent abdominal paragangliomas who carried a germline mutation in PHD2. This mutation affected PHD2 function and stabilized HIFα proteins. LOH in the tumor suggested that PHD2 may act as tumor-suppressor gene.

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Fumarate Hydratase Gene

The fumarate hydratase (FH) gene encoding fumarate hydratase in a pheochromocytoma with an “SDH-like” molecular phenotype has been reported. Five pathogenic germline FH mutations (4 missense and 1 splice mutation) in 5 patients were identified. Remarkably, FH-deficient pheochromocytoma/paraganglioma displays the same pattern of epigenetic deregulation as SDHB-mutated malignant tumors. This suggests that mutation screening for FH should be included in genetic testing for pheochromocytomas/paragangliomas, at least for tumors with malignant behavior.11

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Immunohistochemical Staining in Paraganglioma

Expression of CgA, synaptophysin, tyrosine hydroxylase, S100 in paragangliomas is similar to that in pheochromocytomas. IHC can be used to triage genetic testing of paragangliomas. NESP-55, a chromogranin-related molecule present in endocrine tumors of the pancreas and the adrenal medulla, has not been detected in paragangliomas,107 so this may be a useful marker to separate some neuroendocrine tumors in small biopsy specimens. SDH immunostaining has been helpful in the initial diagnosis of familial paragangliomas. Negative staining is more commonly found associated with SDHB mutations, whereas weak diffuse staining often occurs with SDHD mutation.108,109 The sensitivity and specificity of SDHB IHC to detect the presence of an SDH mutation in a prospective series was very high. Therefore, by routinely performing SDHB IHC the malignant potential of pheochromocytomas/paragangliomas associated with malignancy could be assessed with a high degree of reliability.110

SDHA IHC on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allow for the identification of SDHA-related tumors in a small percentage of pheochromocytomas/paragangliomas.74 Overexpression of HIF1α transcript has been associated with malignant pheochromocytomas and paragangliomas.111

For the general surgical pathologist the use of SDH IHC is probably too specialized for routine use, as potential use of the antibody for particular cases will be uncommon. It should be more practical to send cases to a specialized center for analysis if a familial case is suspected because of the patient’s age or the presence of multiple paragangliomas that are not obvious metastatic lesions.

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Prognosis of Paragangliomas

The classification of paragangliomas as malignant has been based on the identification of distant metastases. Distant metastases occur in about 20% of paragangliomas.112 Laird et al113 proposed that malignant paraganglioma may be more aggressive than malignant pheochromocytomas, and patients with these tumors were frequently offered more adjuvant therapy. Pheochromocytomas and paragangliomas should probably be evaluated separately in future analyses of these tumors.

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Histopathologic Diagnosis of Malignant Pheochromocytomas and Paragangliomas

Between 10% and 30% of pheochromocytomas and paragangliomas metastasize. Although most cases of pheochromocytomas/paragangliomas are surgically curable, malignant tumors represent intractable diseases that are difficult to eradicate. Therefore, reliable histologic features to separate benign and malignant pheochromocytomas and paragangliomas are urgently needed. Morphologic determination of the malignant potential of pheochromocytomas and paragangliomas represents a challenging problem in surgical pathology. Two recent systems have been proposed to predict malignant behavior on the basis of histopathologic findings and are summarized below.

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Pheochromocytoma of the Adrenal Scaled Score

Thompson proposed the Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) system to separate benign from malignant pheochromocytomas based on a clinicopathologic and immunophenotypic study of 100 cases. Fifty histologically malignant and 50 histologically benign pheochromocytomas of the adrenal gland were retrieved from the files of the Armed Forces Institute of Pathology. Histologically, the cases of malignant pheochromocytomas of the adrenal gland more frequently demonstrated larger size, invasion (vascular, capsular, periadrenal adipose tissue), large nests or diffuse growth, and focal or confluent necrosis,114,115 high cellularity, tumor cell spindling, cellular monotony, increased mitotic figures, atypical mitotic figures, profound nuclear pleomorphism, and hyperchromasia compared with benign tumors (Table 1). The PASS system weighted for these specific histologic features could be used to separate tumors with a potential for a biologically aggressive behavior (PASS≥4) from tumors that behave in a benign manner (PASS<4). The pathologic features that are incorporated into the PASS correctly identified tumors with a more aggressive biological behavior.1,116



PASS was an earlier scoring system for the diagnosis of adrenal pheochromocytomas. However, the reproducibility and clinical significance of the PASS system have not been established. A few studies have examined the robustness and, in particular, the potential for observer variation inherent in the interpretation and assessment of these morphologic criteria. Strong et al117 found that a higher threshold of 6 was indicative of malignant behavior but recommended that patients with a PASS score 4 should be closely followed. Wu and colleagues examined the utility of PASS by reviewing an independent single institutional cohort of adrenal pheochromocytomas as evaluated by 5 multi-institutional pathologists with at least 10 years experience in endocrine pathology. Significant interobserver and intraobserver variability in the PASS score with variable interpretation of the underlying components was reported, suggesting that this was not a very reliable approach even for expert endocrine pathologists.118

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Grading System for Adrenal Pheochromocytomas and Paragangliomas

The Pheochromocytoma Study Group in Japan analyzed 163 tumors including 40 metastatic pheochromocytomas and paragangliomas using their Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP) System.110 The tumors were scored on the basis of GAPP criteria as follows: histologic pattern, cellularity, comedo-type necrosis, capsular/vascular invasion, Ki-67 labeling index, and catecholamine type. All tumors were scored from 0 to 10 points (Table 2), and were graded as 1 of 3 types: well differentiated, moderately differentiated, and poorly differentiated (Table 3). GAPP scores of the nonmetastatic and metastatic groups were 2.08±0.17 and 5.33±0.43, (mean±SE, P<0.001), respectively. There was a significant negative correlation between the GAPP score and the time until metastasis (r=−0.438, P<0.01). The mean number of years until metastasis after the initial operation was 5.5±2.6 years. The 5-year survival of these groups was 100%, 66.8%, and 22.4%, respectively. In addition, negative immunoreactivity for SDHB gene was observed in 13 (8%) moderately or poorly differentiated tumors, and 10 of the 13 (77%) had metastases. The authors suggested that a combination of GAPP classification and SDHB IHC might be useful for the prediction of metastasis in these tumors.110 Although this approach looks promising, it will require independent validation in other laboratories to determine its utility in the surgical pathology laboratory. Inclusion of Ki-67 in the criteria for grading pheochromocytomas and paragangliomas indicates the growing importance of the Ki-67 proliferative index in grading and diagnosing neuroendocrine neoplasms.





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A great deal of new information has been learned about pheochromocytomas and paragangliomas during the past decade. Genetic mutations in these tumors include >10 genes involved in their pathogenesis including RET oncogene, involved in the pathogenesis of MEN 2A and 2B, VHL tumor-suppressor gene, neurofibromatosis type 1 gene, SDH, THEM127, H-RAS, KIF1B, HIF2α, PHD2, and FH. Several systems have been proposed to predict the biological behavior of these tumors, and the grading system for adrenal pheochromocytoma and paragangliomas looks promising, but remains to be validated in independent laboratories.

For the general surgical pathologist IHC workup of pheochromocytomas and paragangliomas should include IHC staining for chromogranin, synaptophysin, and S100 protein. Ki-67 immunostaining should also be done to assist in the grading of pheochromocytomas and paragangliomas. However, immunostaining for SDH mutation and molecular analyses of SDH mutations and other mutations should probably be done in specialized centers.

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pheochromocytoma; paraganglioma; multiple endocrine neoplasia type 2; neurofibromatosis; Von Hippel-Lindau disease; THEM127; succinate dehydrogenase; prognosis

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