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Pheochromocytoma is a rare tumor of the adrenal medulla composed of and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. (2025). 9784431728191, Springer Japan. ISBN 9784431728191 These neuroendocrine tumors can be sympathetic, where they release into the bloodstream which cause the most common symptoms, including hypertension (high blood pressure), tachycardia (fast heart rate), sweating, and headaches. Some PGLs may secrete little to no catecholamines, or only secrete paroxysmally (episodically), and other than secretions, PGLs can still become clinically relevant through other secretions or mass effect (most common with head and neck PGL). PGLs of the head and neck are typically parasympathetic and their sympathetic counterparts are predominantly located in the abdomen and pelvis, particularly concentrated at the organ of Zuckerkandl at the bifurcation of the aorta. (2025). 9780323790062, Elsevier–Health Science. ISBN 9780323790062
In pregnancy, pheochromocytoma is associated with significant Maternal death and fetal mortality, mainly due to hypertensive crisis in the mother and intrauterine growth restriction in the fetus.
Misdiagnosis of pheochromocytoma can be deadly, as , often prescribed for hypertension, can lead to unopposed alpha in the context of pheochromocytoma. Most mortality associated with diagnosed pheochromocytoma came from surgery and hypertensive crisis, but mortality has greatly improved.
| +Classic Pheochromocytoma Tumor Syndromes ! !Gene !Inheritance !Penetrance !Metastasis Potential !1o Disease Characteristics |
MEN2 (Multiple Endocrine Neoplasia-2); VHL (von-Hippel Lindau); NF1 (Neurofibromatosis-1); NET (Neuroendocrine Tumor); CNS (Central Nervous System)
| +Hereditary Paraganglioma Syndromes ( SDHx) ! !Gene !Inheritance !Penetrance !Metastasis Potential !1o Disease Characteristics |
| +Other Pheochromocytoma Gene Mutations ! !Inheritance !Penetrance !Metastasis Potential !1o Disease Characteristics |
If a person has the characteristic signs and symptoms of a pheochromocytoma and the decision is made to pursue additional biochemical (blood work) evaluation, the differential diagnosis is important as it is more likely to be something other than a pheochromocytoma given the relative frequency of 0.8 per 100,000 person-years.
While previously suggested "10% of pheochromocytoma can be malignant", this is obsulete, per the most recent classification of pheochromocytoma and paraganglioma by the World Health Organization (WHO) in 2022, thus all patients with phaeochromocytomas are currently considered to have a lifelong risk of metastases and therefore conceptually they are all considered of having 'malignant potential'.
The risk of metastasis ranges from ~5 to 15%. There is no single histological finding or biomarker to reliably predict metastatic disease, and multiparameter scoring systems have been proposed.
| +Differential Diagnosis of Pheochromocytoma by System !scope="col" | Endocrine !scope="col" | Cardiovascular !scope="col" | Neurologic !scope="col" | Psychiatric !scope="col" | Other |
| Hyperthyroidism | Heart failure | Migraine | Anxiety | Porphyria | |
| Carcinoid Syndrome | Stroke | Panic disorder | Medications | ||
| Hypoglycemia | Ischemic Heart Disease | Epilepsy | Substance Use | ||
| Menopause Syndrome | Baroreflex Failure | Meningioma | Factitious Disorder | ||
| Medullary Thyroid Carcinoma | – | POTS | – |
Borderline elevated metanephrines present a diagnostic challenge to the physician — the first step is to repeat the labs, taking extra precautions to follow the gold standard diagnosis described above, including the conditions of collection, pharmaceutical interference, and any potential diet and lifestyle habits that could alter the results. If the offending medications cannot be discontinued or repeated labs remain the same, consider administering a clonidine suppression test. In the 1970s, the drug clonidine hydrocloride swept the market as a novel agent for hypertension; however, the reported side-effects (nausea, vomiting, Somnolence, dryness of the eyes and mouth, constipation, and generalized weakness) limit compliance and have vastly diminished prescriptions. While the adverse side-effects with clonidine are inconvenient, the most dangerous aspect of clonidine is withdrawal rebound hypertension — that is, when the medicine is abruptly discontinued, blood pressure may rapidly return or surpass the original value. However, a one-time, weight-based dose can be utilized in limited settings to help determine disease status. After fasting overnight, patients will present to their testing site for a baseline metanephrines blood draw and clonidine administration. They will remain Supine position for (3) hours, and a repeat blood draw will be taken. A positive result (indicating a pheochromocytoma) will occur if the plasma metanephrine levels remain elevated after clonidine is given. If the results are the same or fall, the test is negative and the patient does not have a pheochromocytoma. It is important to note that if a patient does not have a pheochromocytoma, they may become extremely Hypotension following clonidine. Patients should not depend on themselves for transport following this test.
Plasma methoxytyramine is a breakdown product of the catecholamine dopamine. Paragangliomas of the head and neck commonly secrete dopamine, but are referred to as "biochemically silent" because they do not cause the characteristic symptoms associated with a pheochromocytoma. However, methoxytyramine can be utilized to detect the tumors of the head and neck. Further research indicates that the biomarker is also a useful indicator of Metastasis disease — which is the only current biochemical evidence of metastases to date.
While there has not been a consensus on whether CT or MR is the preferred imaging modality in pheochromocytoma, each method has its associated strengths and weaknesses. As CT expose the patient to ionizing radiation, MR is preferred in children and pregnant women. Furthermore, the Contrast agent used in CT can cause kidney damage and should therefore be avoided in patients with pre-existing damage. However, patients who struggle with being in confined spaces for extended periods (claustrophobia) cannot often tolerate an MR as the machine is close-ended compared to the open-ended design of a CT. When patients become anxious and begin to move in the machine, this causes motion artifact, which occurs less in CT-based images.
Compared to CT and MR, ultrasound is not a preferred imaging modality and should be avoided in the pheochromocytoma patient. However, in specific patient populations where avoiding ionizing radiation is the top priority (children, pregnant women), ultrasound can be used as an adjunct method when MR may be unavailable or the patient is unable to complete the scan. Furthermore, if an acute adrenal hemorrhage is suspected in a pheochromocytoma patient, ultrasound is a quick, painless, radiation-less, and cheap modality for a "first-pass" before the above imaging modalities or surgery is used to confirm the diagnosis.
The first functional imaging technique utilized in pheochromocytoma patients was 123I-Iobenguane scintigraphy. Given the compound's similar structure to the catecholamine norepinephrine (secreted by pheochromocytomas), MIBG was well-suited for uptake by most neuroendocrine tumors. Furthermore, if a patient was found to be positive on an MIBG scan, they were eligible for MIBG treatment, offering additional avenues for those with widespread metastatic disease. However, further investigation revealed that while MIBG excelled with adrenal lesions, it was far less superior in patients with extra-adrenal paragangliomas, particularly with specific Mutation like those in the succinate dehydrogenase subunit–encoding genes (SDHx). As the positron emission tomography scans were developed, MIBG has slowly lost its favor for the pheochromocytoma patient.
Of the four above mentioned modalities, 18F-FDG glucose PET is the most common and readily available functional imaging technique at most hospital systems, but the least-specific to neuroendocrine tumors (Image Left). In 2012, over 200 patients participated in a trial that compared the current gold standard of the time (MIBG/CT/MRI) to the novel FDG PET. Compared to its functional counterpart, FDG outperformed MIBG in detecting soft-tissue and bone metastases with higher specificity in patients with biochemically active tumors.
Following the development of FDG-PET, neuroendocrine-specific PET scans began to emerge. One of the first favorable imaging modalities was 18F-FDOPA, which demonstrated a high sensitivity in detecting head and neck paragangliomas as well as non-metastatic disease outside of the head and neck. Unfortunately, in cases of Metastasis disease, particularly related to succinate dehydrogenase subunit B ( SDHB) mutations, 18F-FDOPA fell inferior to the traditional FDG-PET. However, for patients with genetic variants in other pheochromocytoma-susceptibility genes ( NF1, VHL, RET) 18F-FDOPA has become the preferred radiopharmaceutical agent.
The newest PET modality involves somatostatin receptor type two receptor imaging with 68Ga-DOTA analogues. Over the last decade, further research continues to indicate the superiority of this functional imaging modality in a wide range of clinical scenarios, even surpassing anatomic imaging (CT scan/MR) in pediatric patients with succinate dehydrogenase (SDHx) mutations. While FDOPA inconsistently detected metastatic disease, 68Ga-DOTA analogues have demonstrated superior localization of metastatic pheochromocytoma. When directly compared in one head-to-head study in 2019, 68Ga-DOTA analogues outperformed FDOPA, particularly in the detection of metastatic bone lesions. An additional benefit of the DOTA analogues is the ability for treatment with peptide receptor radionuclide therapy, which will be discussed in the treatment section below.
Also, HED-PET is an accurate tool to diagnose and rule out pheochromocytoma in complex clinical scenarios and to characterise equivocal adrenal tumours.
Immunohistochemical Markers Immunohistochemistry (IHC) plays a critical role in diagnosing pheochromocytomas and paragangliomas. As pheochromocytomas and paragangliomas are composed of different types of cells, such as the chromaffin cells and sustentacular cells, different markers are used to identify each. Tumor cells commonly express neuroendocrine markers such as Chromogranin-A, Synaptophysin, and transcription factors like GATA3, which is particularly significant in identifying sympathoadrenal lineage tumors. Sustentacular cells express SOX10 and S100, with S100 protein being more widely distributed but less specific. Loss of sustentacular cells' markers can be indicative that the lesion is metastatic rather than primary pheochromocytoma or paraganglioma. Molecular markers associated with genetic variants are also utilized in the diagnostic workup. Loss of SDHB staining is indicative of SDHx-related pathogenesis and is particularly noted in tumors with SDHB pathogenic variants. INHA can be a useful marker in identifying tumors driven by hypoxia signaling pathways, such as those with HIF2α mutations. Carbonic anhydrase 9 (CAIX) is employed to assist in diagnosing tumors associated with VHL mutations. Other markers include tyrosine hydroxylase (TH) and dopamine beta-hydroxylase (DBH), both critical in confirming catecholamine-producing tumors. Choline acetyltransferase (ChAT) is noted in parasympathetic paragangliomas, while Ki67 is used to assess proliferative activity and predict the metastatic potential of these tumors.
Given the origin of these tumors (and chromaffin cells) from Neural crest, they can be seen as a composite tumor comprising a second component that is also derived from neural crest. Thus, composite tumors in the context of pheochromocytomas and paragangliomas may contain a developmentally-related tumors such as Ganglioneuroma, ganglioneuroblastoma, Neuroblastoma, schwannoma, or malignant peripheral nerve sheath tumors (MPNST).
Larger tumors, even for those larger than 6.0 cm, can be attempted with a minimally invasive approach, but the team should be prepared to convert to an open procedure if necessary. An Open surgery procedure (traditional surgical technique) is currently preferred for extra-adrenal disease, unless the tumor is small, non-invasive, and in an easy to maneuver location. While previous data indicated the need for a minimally invasive approach with Malignancy and/or Metastasis disease, current research indicates a successful operation is feasible and results in a shorter hospital stay. Literature within the last decade has also demonstrated that the robotic technique may be successfully utilized for .
Typically, complete or total adrenalectomy is performed; however, a technique referred to as "cortical-sparing" can leave a remnant (piece) of the adrenal gland in hopes of avoiding lifelong Prednisone if the left and right adrenal glands need to be removed. The issue is particularly important in patients with MEN and VHL-related disease, which has a higher chance of bilateral pheochromocytomas. The risk of leaving adrenal tissue is recurrent disease (tumor comes back). A 2019 cohort study reported that despite a 13% recurrent rate in patients who underwent a cortical-sparing adrenalectomy for pheochromocytoma, there was no decreased survival compared to their total adrenalectomy counterparts.
In a 2010 survey of 40 endocrinologists by researchers at the Cedars-Sinai Medical Center in Los Angeles, California, nearly all indicated the importance of preoperative volume resuscitation (having the patient take in plenty of fluids before surgery). However, after reviewing their patient data, over 60% of the same physicians failed to discuss salt-loading and adequate hydration. When the patients were stratified by age, those that were younger received the advice to hydrate, but older patients did not. It was Hypothesis that the providers chose to forego volume repletion in the older patient population for fear of their potential Comorbidity (heart failure) where excess fluid is dangerous. While there is still no recognized consensus or gold standard, providers should individualize the decision based on the patient's perceived nutritional standing, volume status, Comorbidity, and ability to self-hydrate.
Cardiovascular
Laparoscopy approach to the original disease, especially in large tumors, has been identified as an important risk factor for tumoral seeding.
Despite all of the potential treatment options, recent literature highlights that (for most patients) metastatic pheochromocytoma is slow-growing. In patients with minimal disease burden, a "Watchful waiting" approach with frequent imaging to monitor disease is favorable, withholding treatment until evidence of progression is visualized.
Surgery — Normally, the goal of surgery is complete cytoreductive surgery; leave no remnant of disease. However, with widespread metastatic disease, this is not always feasible. Therefore, a surgical debulking procedure is performed (removing as much of the cancerous tissue as possible) to reduce patient symptoms by removing the source of catecholamines, improve response to Chemotherapy or radionuclide therapy, or simply decrease the size of the tumor. Unfortunately, the intended relief from the procedure is often short-lived, especially if the patient has disease outside the abdomen. A 2013 study from the National Institutes of Health reported that a majority of patients with recurrent biochemical evidence of disease within one year of the operation and less than 30% continued to be biochemically free of disease after five years.
In contrast to an operation for non-metastatic disease, an open procedure may be preferred over a minimally invasive technique to circumvent potential tumor spread. This also aids surgical visualization and offers the best opportunity to identify and remove metastatic lymph nodes. Reports have also indicated the utility of administering a radionuclide agent like iodine-123 meta-iodobenzylguanadine (123I-MIBG) prior to surgery and then scanning the patient intraoperatively with a probe to detect disease that may be missed with the naked eye. Radiation Therapy — With regard to pheochromocytoma, radiation techniques are primarily used for pain control, specifically with regards to Bone metastasis, local control of the disease, and to limit spinal cord compression. A multidisciplinary team from the Mayo Clinic retrospectively reviewed all of their patients who underwent external beam radiation therapy from 1973 to 2015 and reported that 94% of patients acknowledged symptomatic improvement and over 80% of patients showed no evidence of recurrent disease five years post-therapy. Another report from the same institution looked at almost two decades of patients who underwent radiofrequency ablation, cryoablation, or percutaneous ethanol injection for metastatic pheochromocytoma and reported that local control was achieved in over 85% of targeted lesions and that 92% of procedures were associated with reduced pain and/or symptoms of catecholamine excess.
Chemotherapy — The most common chemotherapy regimen for metastatic pheochromocytoma is cyclophosphamide, vincristine, and dacarbazine, collectively known as CVD. Response to therapy is measured by a reduction in total tumor volume as well as symptomatic relief, reported by the patient. A systematic review and meta-analysis of unstratified pheochromocytoma patients who underwent CVD therapy showed that 37% of patients had a significant reduction in tumor volume, while 40% of patients experienced lower catecholamine burden. While there was no difference in Survival rate between patients whose tumors shrunk versus those without a response (no reduction in tumor burden via imaging), even in non-responders, patients reported feeling better, blood pressure was lower, and some patients were even able to undergo surgery following disease stabilization with CVD. When patients are studied by various categories, research has suggested that females are less likely to have extended survival with CVD chemotherapy compared to their male counterparts. Genetic status has been shown to greatly impact response to CVD. A team of researchers from the National Institutes of Health reported that patients with succinate dehydrogenase subunit B (SDHB) mutations are not only more likely to initially respond to CVD, but that they also experienced over 30 months of progression-free survival (time until tumor returned) with continued administration.
However, CVD is not the only proven chemotherapeutic regimen in the pheochromocytoma patient. A 2018 report demonstrated the remarkable response of two SDHB patients who failed CVD chemotherapy (disease progressed despite medication), but were then treated with temozolomide (TMZ) and had progression free survival of 13 and 27 months, indicating that TMZ can be considered as an alternative treatment regimen in those who have progressed on CVD. Several studies have since reported successful responses with TMZ, particularly in the SDHB sub-population.
Tyrosine Kinase Inhibitor
Tyrosine kinase inhibitors (TKIs) have been explored as therapeutic options for metastatic pheochromocytoma and paraganglioma, targeting VEGF-driven angiogenesis, particularly in cluster 1 tumors. Sunitinib demonstrated a partial response rate of 17% with a median progression-free survival (PFS) of 4.1 months and a lower risk of progression in patients with SDHB pathogenic variants as observed in the FIRSTMAPPP trial. Common side effects included hypertension and cardiovascular complications necessitating antihypertensive pre-treatment. Cabozantinib, assessed in the NATALIE trial, showed a 25% objective response rate and a 93.75% disease control rate with a median PFS of 16.6 months and overall survival (OS) of 24.9 months, but hypertension, fatigue, and diarrhea were frequently reported. Lenvatinib and pazopanib exhibited limited efficacy and significant toxicities in phase 2 trials, while Axitinib achieved a 35.3% partial response rate and a median PFS of 7.9 months in a small trial, though hypertension occurred in 79% of patients. Anlotinib, in a cohort of 37 patients with metastatic and unresectable PPGL, produced a 44.4% partial response rate and a 96.3% disease control rate over a median follow-up of 13.5 months, with hypertension, malaise, and palmar-plantar erythrodysesthesia being the most common adverse events. Combining anlotinib with radionuclide therapy resulted in a 100% disease control rate during the follow-up period.
Radionuclide Therapy
Target Therapies Targeted therapies have emerged as promising treatment options in the management of pheochromocytoma and paraganglioma, particularly for tumors driven by specific pathogenic variants. Belzutifan, a hypoxia-inducible factor 2-α (HIF2α) inhibitor, has demonstrated significant clinical benefit in tumors with EPAS1 pathogenic variants. By targeting the HIF2-α pathway, belzutifan effectively reduces catecholamine levels, stabilizes tumor growth, and mitigates symptoms such as hypertension and tachyarrhythmias, particularly in patients with Pacak-Zhuang syndrome, where EPAS1 gain-of-function mutations are prevalent, with a relatively tolerable profile.
In May 2025, the U.S. Food and Drug Administration approved the HIF-2α inhibitor belzutifan (Welireg) as the first oral systemic treatment for adults and adolescents (≥ 12 years) with locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma. Approval was based on the phase-II LITESPARK-015 trial, which demonstrated a 26 % objective response rate and a median response duration of 20.4 months.
Some patients may experience dose-related anemia, and hypoxia.
Another targeted agent, Selpercatinib, a RET proto-oncogene kinase inhibitor, has shown efficacy in RET-driven tumors, including those associated with multiple endocrine neoplasia type 2 (MEN2). The expanding landscape of targeted therapies provides new avenues for individualized treatment strategies, particularly in genetically defined subgroups of pheochromocytoma and paraganglioma, where traditional systemic therapies have limited efficacy.
Recent literature has detailed several factors that predict accelerated progression of disease and higher mortality rates, including patients who choose to forego surgical resection of their primary tumor, larger tumors at initial presentation, older age at initial diagnosis, and a shortened time from primary tumor to presence of metastases. The actual location of the metastases can also indicate prognosis, with Bone lesions (bone) faring better than their soft-tissue (lung, liver) counterparts.
Despite the prominence in many respected textbooks, these guidelines have since been established as inaccurate and are not used in current epidemiological discussions.
As suggested above, incidental imaging has become a major player in the diagnosis of patients with pheochromocytoma, with current estimates that 10–49% of all cases diagnosed after imaging was obtained for another reason. When an adrenal nodule (potential tumor) is discovered on CT scan or magnetic resonance imaging, there is a 5–10% chance the lesion is a pheochromocytoma. The incidence of adrenal tumors is found in the infographic above, with pheochromocytoma noted in yellow in the top right corner.
While various physicians were recognizing symptoms and treating patients, [[Czech|Czech Republic]] biologist [[Alfred Kohn]] reported his discovery of the [[paraganglia|Paraganglion]] system, which would later become crucial to the diagnosis of these tumors. Furthermore, he also introduced the term "[[chromaffin|Chromaffin cell]]," allowing pathologists to recognize tumors that arose from the [[adrenal gland]].(2025). 9780444536167, Elsevier. ISBN 9780444536167
In 1908, two Pathology, Henri Alezais and Felix Peyron, introduced the scientific community to "paraganglioma" after they discovered extra-adrenal tissue that reacted to chromium salts, which mimicked the reaction of the adrenal medulla. Just four years later, German pathologist Ludwig Pick coined the term "pheochromocytoma" after he observed the consistent color change in tumors associated with the adrenal medulla. Many surgeons attempted to remove these tumors over the next decade, but their patients died intraoperatively from shock. In 1926, Charles Mayo (a founder of the Mayo Clinic) became the first physician to successfully excise a pheochromocytoma. However, Mayo was likely unaware of the diagnosis before the operation. Not until 1929 was a pheochromocytoma recognized preoperatively. Throughout the early 1900s, the operative mortality rate for a pheochromocytoma ranged from 30 to 45%. Retrospective series have postulated that these alarmingly high death rates were due to the lack of a pre-operative blockade with alpha and beta-adrenoceptor antagonist and the need for modern anesthesia practices. From this point forward, physician-scientists have been recognizing patterns in patients with pheochromocytoma and identifying genetic associations and various syndromes.
The National Organization for Rare Disorders is a United States–based advocacy parent organization to promote awareness and research opportunities to cure rare diseases. Groups such as these encourage patients to become their advocates and change agents in their healthcare decision-making processes.
In the seventh and eighth seasons of Grey's Anatomy, series regular Henry has a Von Hippel-Lindau (VHL) mutation that has resulted in a pheochromocytoma. The story arc was met with mixed opinions from the rare disease community. The executive director of the VHL Alliance was happy with the portrayal of a VHL patient in mainstream media, but pointed out that of the four scripts she knew of with a VHL patient, three involved a pheochromocytoma, which occurs in less than a fifth of all VHL patients.
A case of pheochromocytoma was featured in the first episode of season 2 of House, M.D.. Gregory House and his team are tasked with diagnosing and treating an inmate on death row. Although the patient has a violent history of homicide, Dr. House suspects that his episodic rage and aggression may be caused by an adrenaline secreting tumor. Dr. House is able to locate the tumor and diagnoses the patient with pheochromocytoma. Dr. Foreman, one of the doctors, attempts to appeal the inmate's death penalty on the basis that he was unable to control his actions due to his tumor. This kind of insanity defense is rarely successful, however.
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