Pheochromocytomas (PCCs) and paragangliomas (PGLs) arise from chromafin cells originating in the neural crest, and can develop in any location containing sympathetic or parasympathetic tissue. Although the terminology is not completely standardized, PCC typically refers to tumors of adrenal origin while PGL describes lesions found outside the adrenal gland. While most PCC and PGL are benign, malignant disease does occur and is distinguished by behavior such as metastasis and invasion into other structures. Identifying benign disease with potential to become malignant is exceedingly difficult as there is currently no reliable gene signature or histologic feature that clearly identifies malignancy. Even more importantly, metastasis can occur 15 to 20 years after resection of apparently benign disease, and this makes it difficult to accurately study PCC and predict malignancy.

The estimated incidence of PCC and PGL ranges from 0.4 to 9.5 per 1 million.¹ Although PCC is traditionally considered a tumor of 10s with 10% being malignant, the actual incidence may be greater than 25% depending on the characteristics of the population being studied.² Specific mutations (see below) confer heightened risk for malignancy while others are very rarely associated with cancer. The peak age for diagnosis is in the third decade of life with men and women at equal risk. Recent developments in gene sequencing technology have demonstrated that 20% to 30% of even sporadic appearing PCC and PGL carry a hereditary component, and this has prompted some to recommend referral to genetic counselors for any individual diagnosed with PCC or PGL.^3–5

Despite being a rare disease, a remarkable number of mutations that increase risk of developing PCC and PGL have now been identified. These genes are associated with distinct clinical syndromes and differing risk of malignancy (Table 43-1).

Succinate Dehydrogenase

Succinate dehydrogenase (SDH) plays an important role in the electron transport chain and the Krebs cycle. When adequate oxygen is available, SDH catalyzes conversion of succinate to fumarate and generates ATP for cellular metabolism.⁶ Under conditions of oxygen deprivation, however, cell functions using anaerobic metabolism and succinate levels rise. This leads to stabilization of hypoxia-inducible factor 1 (HIF-1) which triggers a downstream cascade to increase vascularization via factors such as VEGF and restores a state of oxygen metabolism.⁷ Since the SDH enzyme complex converts succinate to fumarate, mutations can result in accumulation of succinate and reactive oxygen species. Consequently, mutations in various SDH subunits result in a state of pseudohypoxia where HIF-1 triggers activity of vasculogenic transcription factors. This could potentially promote tumor growth via angiogenesis.

SDHA

Mutations in SDH subunit A (SDHA) have been found in PGL and occasional PCC.^8–9 This represents a relatively rare autosomal dominant mutation found in approximately 1% of cases. SDHAF2 mutations are found in patients with PGL and are associated with the presence of multiple lesions. Alterations in SDHA have been associated with malignant disease, but this is a relatively rare event. Interestingly, SDHAF2 mutations have a pattern of maternal imprinting rather than the dominant pattern of the SDHA mutation.¹⁰

SDHB

Mutations in the B subunit of SDH (SDHB) are more common than SDHA mutations and appear in around 5% of patients with PCC or PGL. These patients are more likely to have PGL than PCC, often have multiple lesions, and present at an earlier age than sporadic PCC/PGL. From a clinical standpoint, mutations in SDHB are significant because they confer a greater than 40% risk of malignancy. Inheritance is autosomal dominant, and this mutation is also associated with development of renal cell carcinoma and GISTs. ^2,11–14

SDHC

Mutations in SDH subunit C (SDHC) appear in 1% of PCC and PGL and are inherited in an autosomal dominant fashion. Patients generally present with head and neck PGLs, though there is some association with PCC. The risk of malignancy does not appear to be increased in these patients.^14–16

SDHD

Mutations in SDH subunit D (SDHD) are found almost as frequently as SDHB but have maternal imprinting. SDHD mutations are associated with an approximately equal likelihood of PCC or PGL and have a low risk of malignancy, although multiple lesions are present in nearly 60%.^2,14,17,18

RET

Mutations in the RET proto-oncogene are inherited in an autosomal dominant fashion and are associated with increased risk of PCC along with medullary thyroid cancer and parathyroid hyperplasia (multiple endocrine neoplasia type 2). Germline mutations in RET account for 20% to 30% of all cases of medullary thyroid cancer. The RET protein functions as a transmembrane tyrosine kinase receptor that activates downstream factors including P13-Kinase, AKT, and mTOR as well as the Ras-Raf-MEK pathway to promote cell proliferation. Around 50% of patients with RET mutations develop PCC and frequently have bilateral disease. Risk of malignancy in this population is less than 5%.³

VHL Syndrome

von Hippel–Lindau (VHL) syndrome is inherited in an autosomal dominant fashion and is associated with multiple tumors including hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine tumors, and PCC/PGL. Wild-type VHL protein is part of a complex binding and targeting HIF-1 for ubiquitination and proteasome degradation. Mutations in VHL, therefore, lead to increased levels of HIF-1 and create a similar pseudohypoxia phenotype as SDH mutations. These mutations are associated with both benign and malignant PCC/PGL and carry an increased risk of bilateral/multifocal disease.¹⁹

TMEM127

The TMEM127 gene encodes a transmembrane protein which may be involved in protein trafficking. The wild-type protein limits mTORC1 activation via dephosphorylation and, therefore, regulates cell proliferation. TMEM127 mutations are inherited in an autosomal dominant fashion and are associated with increased risk of PCC (with up to 50% having bilateral disease) as well as PGL and are associated with low risk of malignant disease.^20–22

MAX

The MAX protein is a member of the basic helix-loop-helix family of transcription factors and heterodimerizes with members of the MYC and MXD1 protein families. MAX-MYC heterodimers activate transcription of target genes while MAX-MXD1 dimers inhibit MYC-related transcription and block cell proliferation. MAX mutations are found in around 1% of sporadic PCC and patients typically present with PCC, although PGL can also be found. Around 50% of patients will have bilateral PCC and the largest series of MAX mutations to date showed that 10% of patients developed malignancy.^23,24

NF1

NF1 mutations are seen in von Recklinghausen’s disease and neurofibromatosis and are inherited in autosomal dominant fashion. In addition to gliomas, astrocytomas, carcinoids, neurofibromas, and sarcomas, up to 13% eventually develop PCC. These are primarily solitary adrenal lesions, though occasional patients are found with extra-adrenal or bilateral disease. The NF1 gene encodes the protein neurofibromin which regulates p21-Ras to control cellular proliferation and apoptosis. Consequently, about 10% of patients with mutations in NF1 develop malignant PCC.^25,26

It is important to note that there is currently no definitive method of distinguishing benign from malignant PCC based solely on pathology. Instead, diagnosis of malignancy is established based on tumor behavior including metastasis or local invasion. One marker associated with malignancy is the Ki-67 proliferative index, with a value of >3% considered reasonable evidence of malignancy.¹ While a value >3% indicates that benign disease is unlikely, malignant PCC and PGL have been found in lesions with Ki-67 <3%. Consequently, the sensitivity for malignancy is too low to serve as a stand-alone indicator for cancer. The Pheochromocytoma of the Adrenal Gland Scoring Scale (PASS) score is often used to assess probability of malignancy and consists of assigning points based on the presence of large nests or diffuse growth, tumor necrosis, cellularity, tumor cell spindling, cellular monotony, number of mitotic figures, extension into adipose tissue, vascular or capsular invasion, nuclear pleomorphism, and nuclear hyperchromasia. A score of ≥4 was identified as a strong predictor of malignancy while benign lesions were well identified by a score of 3 or less.²⁷ Subsequent analysis of the PASS score by Wu et al,²⁸ however, showed considerable intraobserver variation and less success at identifying malignancy, so work is still underway to identify predictors of malignancy. Kimura et al²⁹ developed a different scoring system based on histologic pattern, degree of cellularity, presence of coagulation necrosis, vascular/capsular invasion, Ki-67 reactivity >3%, and type of catecholamine secretion to categorize tumors as well, moderately, or poorly differentiated. They found that the percentage of metastatic tumors increased from 13% in well-differentiated tumors to 100% in the six poorly differentiated tumors. While promising, this score also needs additional study in a larger external sample in order to be adequately validated. In summary, current pathological scoring systems have some utility in identifying risk of malignancy but are far from ideal. Additional work combining genetic and pathologic markers may eventually yield better results.

Pheochromocytoma classically presents with episodic hypertension along with headache, diaphoresis, pallor, flushing, and palpitations.³⁰ Other common symptoms include pallor, nausea, fatigue, anxiety/panic attacks, and weight loss. Since PGLs frequently lack catecholamine hypersecretion, they are frequently asymptomatic and discovered on imaging. Many of these symptoms can be mistaken for other disorders such as anxiety, essential hypertension, or allergic reactions. Therefore, the diagnosis of PCC or PGL is frequently delayed. Current guidelines recommend workup for surgical causes for hypertension when new-onset hypertension is diagnosed in a young or elderly patient, remains uncontrolled despite adherence to optimal dose of three medications including a diuretic, or when hypertension has a severe or accelerated course.³¹

Following resection of benign PCC/PGL, 10-year recurrence rates may be as high as 20%, with higher rates noted in patients with familial disease or large tumors at presentation. Recurrence can be noted more than 5 years after resection of the original tumor. Even more importantly, lesions that initially appeared to be benign can present with metastasis 15 to 20 years after the initial diagnosis.^11,32–37 Consequently, lifetime surveillance is mandatory in any patient diagnosed with PCC or PGL. Currently, the American Association of Clinical Endocrinologists (AACE)/American Association of Engineering Societies (AAES) guidelines recommend at least yearly follow-up after resection, but no firm recommendations are made regarding the optimal combination of biochemical or imaging modalities.³⁸