Pheochromocytoma

The symptoms of a sympathetic pheochromocytoma are related to sympathetic nervous system hyperactivity. The classic triad includes headaches (likely related to elevated blood pressure, or hypertension), tachycardia/elevated heart rate, and hyperhidrosis (excessive sweating, particularly at night). Attacks can occur spontaneously (without warning) or may be triggered by a variety of pharmaceutical agents (including histamine, metoclopramide, glucagon, and adrenocorticotropic hormone), foods that contain tyramine (cheese and wine), intraoperative tumor manipulation, intubation, or during anesthetic induction. (center, red) is the origin of the pheochromocytoma. Other clinical manifestations that have been reported include (in no particular order): It is estimated that approximately 0.1% of patients with hypertension have a pheochromocytoma, and it is often misdiagnosed as essential hypertension. The cardiovascular system is the most commonly involved. In pregnancy, pheochromocytoma is associated with significant maternal 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 beta blockers, often prescribed for hypertension, can lead to unopposed alpha-adrenergic receptor stimulation in the context of pheochromocytoma. Most mortality associated with diagnosed pheochromocytoma came from surgery and hypertensive crisis, but mortality has greatly improved. Cardiovascular system • Hypertensive crisis: Pheochromocytoma-related hypertensive emergencies are one of the most feared clinical manifestations. Attacks are random and may occur secondary to a trigger (see Signs and Symptoms above) or spontaneously after a catecholamine surge. As with the other cardiovascular-related complications, excess catecholamines are responsible for the increased myocardial burden and significant physiologic stress. Current literature indicates that most of the catecholamine-induced damage is reversible, thereby strengthening the argument for early and accurate diagnosis to allow for cardiac remodeling and prevent further destruction. In a study of 130 patients with pheochromocytoma, 7 patients were diagnosed with a transient ischemic attack (the neurologic deficit completely resolved), and 3 patients experienced a stroke with persistent symptoms. • Headache: Headaches are one of the core clinical manifestations of a pheochromocytoma and can result in debilitating pain. Urinary system • Acute renal failure: Several reports have detailed rhabdomyolysis (rapid skeletal muscle breakdown) leading to acute kidney injury and the need for transient dialysis in the undiagnosed pheochromocytoma patient as their primary presenting symptom. Kidney failure is brought about by catecholamine-induced muscle injury. Norepinephrine causes vessels to narrow, thereby limiting blood flow and inducing ischemia.: Caused by an elevated inflammatory response, multiple organ dysfunction is a severe, life-threatening emergency with increasing mortality based on the number of systems involved. Pheochromocytoma-related MODS is associated with multiple organ failure, hyperthermia > 40 degrees Celsius, neurologic manifestations, and cardiovascular instability resulting in either hypo- or hypertension. In contrast to a hypertensive crisis, pheochromocytoma-associated MODS may not respond to traditional alpha-receptor agents and may require emergent surgical excision if clinical stability is not achieved. ==Genetics==

Current estimates predict that upwards of 40% of all pheochromocytomas are related to an inherited germline susceptibility mutation. Of the remaining 60% of tumors, more than 30% are associated with a somatic mutation. Given the high association with genetic inheritance, the United States Endocrine Society recommends that all patients diagnosed with a pheochromocytoma undergo an evaluation with a genetic counselor to consider genetic testing. In the UK, eligibility for NHS-funded genetic testing is determined by criteria set by the NHS England Genomics service. The criteria in 2024 included all patients with paraganglioma and all patients with unilateral pheochromocytoma aged under 60. The most recent data indicates that there are 25 pheochromocytoma susceptibility genes; however, just 12 are recognized as part of a well-known syndrome. There is no current consensus for how and when asymptomatic carriers (individual who has a genetic variant associated with pheochromocytoma, but no current evidence of disease) should be evaluated. Conversations should occur individually with the patient and their provider to develop a personalized screening plan, alternating between a biochemical (blood work) evaluation and whole-body imaging to monitor disease progression. Pediatric considerations Additional practices may help maintain the emotional and psychological well-being of the minor. Screening includes a multidisciplinary team (endocrinologist, oncologist, psychologist, geneticist, parent, and child) where the primary focus is supporting the child. • A positive result from testing during family-observed days of celebration may mask the happiness associated with these events in the future. • Testing one pediatric sibling at a time allows the family to narrow their focus when results are returned and support each sibling individually. • A negative result may upset a child if their sibling was positive; an opportunity to ask questions and process results may be helpful. Hereditary syndromes The following table(s) detail the clinical characteristics of the well-known hereditary pheochromocytoma gene variants MEN2 (Multiple Endocrine Neoplasia-2); VHL (von-Hippel Lindau); NF1 (Neurofibromatosis-1); NET (Neuroendocrine Tumor); CNS (Central Nervous System) SDHx (Succinate Dehydrogenase Subunit x) Other gene variants There have been several published case reports of other, rare pheochromocytoma-associated susceptibility genes: • Pacak–Zhuang Syndrome • Hypoxia-inducible factor 2 alpha (HIF2A) • Polycythemia • Duodenal somatostatinoma • Retinal and choroidal vascular changes • Paraganglioma/Pheochromocytoma • Pheochromocytoma and Giant Cell Tumor of Bone • H3 histone, family 3A (H3F3A), post-zygotic G34W • Pheochromocytoma/Paraganglioma • Carney Triad • Gastrointestinal stromal tumor • Pulmonary chondroma • Paraganglioma • Carney-Stratakis Syndrome • Gastrointestinal stromal tumor • Paraganglioma Several additional gene variants have been described, but the provided information is inconsistent, and a consensus has not been reached in the community on whether these mutations are truly pheochromocytoma susceptibility genes. ==Diagnosis==

Differential The typical primary symptom is hypertension, which may be either episodic or continual. A diagnosis of pheochromocytoma should be suspected when the patient simultaneously presents with hypertension and the classic triad of heart palpitations, headaches, and profuse sweating. 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. Notes Biochemical evaluation Gold standard Elevated plasma free metanephrines is considered the gold standard diagnosis for pheochromocytoma. Over 10 studies have confirmed that the sensitivity and specificity of this test is 97% and 93% respectively; however, there is still concern for false positive results in the correct clinical scenario. • Conditions of Collection: Unlike many routine laboratory tests that can be drawn at a moment's notice, there are several recommendations that should be followed to ensure the ideal conditions and an accurate sample. Current research indicates that blood work should only be drawn after a patient has been resting supine (flat on their back) for 30 minutes before collection. Specific supine reference values should be used in this scenario. Ensuring these conditions is difficult and may be cost-prohibitive at most institutions. In these cases, a rested, supine draw can be repeated following a positive result in a seated position to eliminate false-positive results. As the majority of these medications are commonly prescribed for psychiatric conditions, a conversation with the prescriber may be necessary to facilitate alternative therapeutic options while the patient is undergoing evaluation for a pheochromocytoma. While the above (3) conditions are likely to contribute to false-positive results if not controlled for, any value greater than 3 to 4 times the upper reference limit of normal should be considered diagnostic for a pheochromocytoma. Other additional biomarkers can be helpful to aid in the diagnosis of pheochromocytoma as well, most notable is Chromogranin A. In comparison to the specificity of elevated catecholamines in the pheochromocytoma patient, chromogranin A is a non-specific polypeptide that is high in a variety of neuroendocrine tumors. However, a 2006 report from Italy found that over 90% of studied pheochromocytoma patients demonstrated elevated chromogranin A levels. If metanephrine values are equivocal, chromogranin A can be used as an adjunct marker to predict the presence of a tumor. 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, drowsiness, 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. Further research indicates that the biomarker is also a useful indicator of metastatic disease — which is the only current biochemical evidence of metastases to date. • Adrenergic (Epinephrine and metanephrine) • More likely to indicate an adrenal tumor • When plasma metanephrine levels were elevated to greater than 15% of the combined levels of normetanephrine and metanephrine, an adrenal tumor or a recurrence of an adrenal tumor that had already been excised can be predicted • Patients are more likely to present with the classic, paroxysmal (episodic) symptoms described above • Common in patients with von-Hippel Lindau and succinate dehydrogenase subunit X genetic variants Traditionally, a patient presents to their physician for symptoms concerning for a pheochromocytoma, which prompts a biochemical evaluation. If the results are positive, the patient is referred for anatomic imaging with a CT or MR scan. However, as anatomic imaging becomes more readily available, patients are referred to an endocrinologist after an incidental (unanticipated finding) adrenal nodule is found on a scan ordered for another reason. 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. Functional imaging The imaging modalities discussed below are for tumor characterization, confirmation of metastatic disease, and treatment planning — they are not used to discern tumor location or help the surgical team prepare for excision. For most pheochromocytoma patients, functional imaging will follow a CT or MR. If anatomic imaging only demonstrates an adrenal tumor without evidence of disease anywhere else in the body and the metanephrine levels are overtly elevated, functional imaging can be foregone in favor of prompt surgical excision. Over the last decade, there have been five functional techniques used to evaluate the pheochromocytoma patient (1) 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET), commonly referred to as the PET scan, (2) iodine-123 meta-iodobenzylguanadine (123I-MIBG), (3) 18F-flurodihydroxyphenylalanine (18F-FDOPA),(4) 68Ga-DOTA coupled somatostatin analogs (68Ga-DOTA),(5). 11C-Hydroxy ephedrine(HED-PET). — the pheochromocytoma is appreciated in the left panel on the right side of the screen (right panel; left side of the screen) as the darkened circle towards the abdomen. The darkened structure at the head of the patient is the thyroid gland, while the darkened structure in the pelvis of the patient is the bladder. This is normal physiologic uptake. |alt=|284x284px The first functional imaging technique utilized in pheochromocytoma patients was 123I-MIBG 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 genetic variants 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. Unfortunately, in cases of metastatic 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/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. ==Pathology==

Paragangliomas and pheochromocytomas exhibit a characteristic nested (Zellballen), trabecular, or solid arrangement of tumor cells, with nests outlined by sustentacular cells that are best visualized using S100 immunostain. The tumor cells are typically large, polygonal, and uniform but may also display extensive vacuolation. The cytoplasm is abundant and finely granular, ranging in coloration from red to purple. Pigmented granules containing hemosiderin, melanin, neuromelanin, and lipofuscin may also be observed. Nuclei can vary extensively in size and shape, presenting as round to oval with prominent nucleoli. 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. Inhibin A 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. ==Treatment==

Surgery Surgical resection is the only curative option for pheochromocytoma as of 2019. A successful excision is a multidisciplinary effort involving the endocrinologist and the patient pre-operatively (discussed below) and the surgical team and anesthesiologist intraoperatively. Without frequent and adequate communication between all of the above-mentioned teams, a favorable outcome is much more difficult. For outcomes such as all-cause mortality, early morbidity, socioeconomic effects, and operative and postoperative parameters, the evidence is uncertain about the effects of either intervention over the other. An open 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 malignant and/or metastatic 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 adrenal tumors. 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 steroid replacement 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. While an eruption can occur at any time, two of the most common triggers are anesthesia and direct tumor manipulation, making surgery one of the most dangerous times for a pheochromocytoma patient if not properly prepared. To help circumvent a catecholamine-crisis, the United States Endocrine Society recommends that all patients with functional (hormonally active) tumors be started on a pre-operative alpha-adrenoceptor blockade a minimum of seven days before surgery. There are several medication options depending on the clinical scenario, each with its own associated strengths and weaknesses. Alpha blockade If the patient's blood pressure is moderately elevated, a selective, short-acting alpha-1 adrenoceptor antagonist (doxazosin, prazosin, terazosin) is the preferred agent. These effects will decrease with time, but providers can try to avoid them by starting at a low dose and slowly increasing until they reach their desired amount. In patients with uncontrolled hypertension, the non-selective alpha-1 and 2 adrenoceptor antagonist (phenoxybenzamine) should be utilized. While uncommon, patients may have a hormonally-active pheochromocytoma and a normal blood pressure. One comparison from 2014 found that a small dose of a calcium-channel blocker (such as amlodipine) may be used pre-operatively in some people. This will not drastically lower the patient's blood pressure and make them hypotensive, but it will assist the surgical and anesthesia teams if there is hemodynamic instability during the operation. Beta blockade An elevated heart rate (tachycardia) and the feeling of a racing heart (palpitations) may follow after initiating an alpha-adrenoceptor antagonist. If that is the case, a beta-adrenoceptor antagonist is then prescribed to control the heart rate. Complications Beta-adrenoceptor antagonists should not be given alone in a pheochromocytoma patient — this can lead to severe consequences. In 1995, a team of physicians from London described the death of a person who had been recently diagnosed with pheochromocytoma after initiation of propranolol, a non-selective beta blocker. She quickly developed a hypertensive crisis leading to shock, myocardial infarction, heart failure, and dense right hemiplegia. Despite attempts at resuscitation, the person died several days later. This complication is related to the impact that alpha and beta-adrenoceptor antagonists have on blood vessels combined with the actions of catecholamines. The normal blood vessel is open, allowing for adequate blood flow. When catecholamines activate the alpha receptor, the vessel constricts (gets smaller), which results in hypertension. However, when catecholamines activate the beta receptor, the blood vessel dilates (gets larger) and allows for increased blood flow, reducing the blood pressure. If a pheochromocytoma patient is only started on a beta-adrenoceptor antagonist, this reverses the protective vasodilation and worsens the patient's hypertension. Controversy While the pre-operative alpha and beta blockade discussed above is overwhelmingly recognized as the standard of care, particularly in the United States, there has been discussion at the international level about whether alpha-blockade is necessary. In 2017, a team of researchers from Germany published an observational case series that called into question the current recommendations for alpha-blockade. The study examined the intraoperative maximal systolic arterial pressure in people with and without alpha-adrenoceptor blockade and found no difference in complications between the two groups. These articles resulted in rebuttals from research teams in the United States, but an international consensus has not yet been reached. Perioperative fluid status Excess catecholamines cause a decrease in the total blood volume, making a patient vulnerable to hypotension during the operation. Therefore, a high-sodium diet with adequate fluid intake should be encouraged prior to surgery. Some institutions in the United States will even admit patients the night prior to surgery for intravenous fluid replacement starting at midnight until the time of the operation. 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 hypothesized that the providers chose to forego volume repletion in the older patient population for fear of their potential comorbidities (heart failure) where excess fluid is dangerous. Cardiovascular • Hypertension: In the pheochromocytoma patient, postoperative hypertension could indicate incomplete tumor resection or another tumor of unknown location. However, the traditional, non-specific causes of postoperative hypertension, including pain, fluid overload, and essential hypertension must also be considered. A perioperative hypertensive crisis is first treated with a 5.0 milligram (mg) intravenous bolus of phentolamine, with additional 5.0 mg dose every ten minutes until the blood pressure falls within an acceptable range. If the blood pressure is only minimally elevated, the patient can resume their alpha and beta-adrenoceptor antagonist from before surgery. A retrospective analysis of beta blocker found that some beta blocker use may cause people to be more prone to hypoglycemia and not experience these symptoms, which could delay the diagnosis. • Adrenal Insufficiency: Following a bilateral adrenalectomy (left and right), the patient is no longer capable of secreting the necessary hormones to keep their body functioning. Life-long steroid (hydrocortisone and fludrocortisone) oral supplementation may be required to ensure they do not develop adrenal insufficiency. When the body is stressed (during surgery), the adrenal glands naturally produce more steroids; however, if the glands have been removed, they are unable to do so. Therefore, "stress-dosing" steroids are required and should be started intraoperatively to mimic the natural physiology of the adrenal glands. The typical regimen when post-operative adrenal insufficiency is thought to be likely: • Those who have lost both their adrenal glands will also require another steroid (mineralcorticoid replacement). The typical daily dose is between 50 and 200 micrograms of fludrocortisone There have been many other reported complications (renal failure, heart failure, intestinal pseudo-obstruction) following tumor resection. However, the above are more likely to be encountered, which is why their management has been specifically outlined here in this article. ==Metastatic disease==

Diagnosis and location Metastatic pheochromocytoma is defined as the presence of tumor cells (chromaffin tissue) where they are not normally found. Patients with a paraganglioma are more likely to develop metastases than those with a pheochromocytoma. The most common extra-adrenal sites of metastases are the lymph nodes, lung, liver, and bone. There have been several studied risk factors associated with the development of metastatic disease — while the patients genetic background plays an important role, the initial age of presentation and size of the tumor lead to negative outcomes. Laparoscopic 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 "watch and wait" approach with frequent imaging to monitor disease is favorable, withholding treatment until evidence of progression is visualized. Treatment Metastatic pheochromocytoma is best managed with a multidisciplinary team of oncologists, surgeons, radiologists, nuclear medicine physicians, and endocrinologists. There are several treatment options available to patients depending on the amount and location of disease: Surgery — Normally, the goal of surgery is complete cytoreductive surgery; 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 chemo 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. 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 metastases, 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. 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 • Iodine-131 meta-iodobenzylguanadine (MIBG) • As was mentioned in the functional imaging section above, MIBG is not only useful in locating the presence of metastatic disease, but also as an available treatment modality. In 2019, a multi-center phase 2 trial looked at the safety and efficacy of MIBG therapy in metastatic or unresectable (not conducive to surgery) pheochromocytoma patients, and the results were promising. Median overall survival was 36.7 months, and 92% of patients had at least a partial positive response (tumor shrinkage) or stable disease without progression within the first year of the study. Furthermore, over a fourth of the patients could decrease their anti-hypertensive medications and reported symptomatic improvement. As MIBG therapy can destroy the thyroid, protective medications (potassium iodide) are started before treatment and need to be continued for at least three weeks after therapy concludes. • Peptide Receptor Radionuclide Therapy (PRRT) • The newest of the treatment options, PRRT, utilizes the 68-Ga DOTA analogues mentioned above in the functional imaging section. Treatment with 177Lu-DOTATATE first demonstrated success in patients with undifferentiated neuroendocrine tumors and then trials began with metastatic pheochromocytoma patients. In 2019, Vyakaranam et al. published favourable results for their 22 patients who underwent PRRT, with partial response in 2 patients and stable disease (no progression) in the remaining 20 patients. Overall toxicity was low, with no high-grade haematological (blood) or kidney damage reported. Newer reports have detailed the utility of combining 90Y-DOTATATE with the traditionally studied 177Lu analog and the various possibilities and novel treatment options these combinations will bring to the field. 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. == Prognosis ==

According to the National Cancer Institute, prognosis is defined as the likely outcome of a disease OR, the chance of recovery or a recurrence. This is an extremely difficult question when it comes to pheochromocytoma, and the answer depends on the patients genetic status, presence of metastatic disease, and the location of their primary tumor. An article about prognosis published in 2000 reported a 91% 5-year survival rate in their patient population; however, over 86% of their patients had sporadic tumors (no known genetic mutation), which commonly have low malignant potential. In 2019, a consortium of almost twenty European medical centers looked at the prognosis of malignant pheochromocytoma and the data starkly varies from the report of sporadic, single tumors, with a median survival of 6.7 years. Overall survival improved if the patient had (1) disease of the head and neck compared to abdomen, (2) less than 40 years of age, (3) and if their biochemistry was less than five times the upper reference limit of normal. The actual location of the metastases can also indicate prognosis, with osseous lesions (bone) faring better than their soft-tissue (lung, liver) counterparts. ==Epidemiology==

According to the North American Neuroendocrine Tumor Society, the prevalence of pheochromocytoma is between 1:2,500 and 1:6,500, meaning that for every 2,500–6,500 people, there is (on average) one person with pheochromocytoma. In the United States, this equates to an annual incidence (new cases per year) of 500 to 1,600 cases. Outside of the United States, several countries have documented their own epidemiological studies and compared them to what is known in North America. In the first national, epidemiological population-based study in Asia utilizing Korean National Health Insurance Service data, the prevalence of a pheochromocytoma was reported at 2.13 per 100,000 persons with an incidence of 0.18 per 100,000 person-years. This is lower than the occurrence reported from Rochester, Minnesota (0.8 per 100,000 person-years), in a study conducted from 1950 to 1979. Current hypotheses for why the incidence of pheochromocytoma is growing in the Dutch population point to the advent of modern imaging evaluation and the ability to detect these tumors before death. While each of the above studies reported varying incidence and prevalence values, all have indicated that the average age at initial diagnosis is between the third to fifth decade of life. When younger patients are diagnosed with a pheochromocytoma, there should be a high suspicion for hereditary disease, as genetic anticipation (earlier disease onset with each generation) is associated with some mutations. Classically, the pheochromocytoma "rules of 10" have been taught, particularly to medical students: • 10% of patients have malignant disease • 10% of patients have bilateral (both left and right adrenal glands) disease • 10% of patients have extra-adrenal (paraganglioma) disease • 10% of patients have inherited (familial disease) 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 computed tomography 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. ==History==

, pathologist who performed the first histological description of pheochromocytoma in 1886 In 1800, an Irish physician (Charles Sugrue) penned a case report to the London Medical and Physical Journal describing the peculiar case of an 8-year-old male patient who had had seemingly random fits of pain concentrated in the abdomen accompanied by "a hectic flush distinctly marked on each cheek" with a "constant profuse and universal perspiration." Following his death, a group of physicians performed an autopsy to determine cause of death and discovered a six-inch oblong tumor composed of an unknown "yellow-ish coloured substance" coming from the capsula renalis (what is now known as the adrenal gland). Following the initial 1886 monograph by Fraenkel and colleagues describing "sarcoma and angio-sarcoma" in the 18-year-old female, a group of investigators led by Hartmut Neumann in 2007 traced the patient's family members and identified a pathogenic variant in the RET proto-oncogene (p.C634W), associated with Multiple endocrine neoplasia type 2. While various physicians were recognizing symptoms and treating patients, Czech biologist Alfred Kohn reported his discovery of the paraganglia system, which would later become crucial to the diagnosis of these tumors. Furthermore, he also introduced the term "chromaffin," allowing pathologists to recognize tumors that arose from the adrenal gland. In 1908, two pathologists, 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. From this point forward, physician-scientists have been recognizing patterns in patients with pheochromocytoma and identifying genetic associations and various syndromes. ==Society and culture==

While a rare disease, there have been several references to pheochromocytoma in popular culture and the media, specifically medical television dramas. Additionally, there is a strong online patient advocacy community that works to connect patients with rare diseases and allows them to meet other individuals who are experiencing similar diagnoses and treatment strategies. Zebra culture In the medical community, students are often taught "when you hear hoofbeats, think horses, not zebras." In other words, common diagnoses are common, so healthcare professionals should first rule out what is most expected (the horses) before diving into the rare etiologies that are far less likely to be correct (the zebras). However, the symbol of the zebra has become increasingly powerful to the rare disease community and resulted in several organizations, societies, and special events (Rare Disease Day) to draw attention to the least common option sometimes being the correct diagnosis. 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. Media In July 2012, an actual pheochromocytoma patient, Tannis Brown, former vice-president of the PheoPara Troopers, was featured on the Discovery Fit & Health Network program Diagnosis: Dead or Alive. The show highlighted her personal struggle with misdiagnosed disease as many physicians felt her episodic headaches and hypertension (high blood pressure) were related to stress. 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.. Dr. 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 legal defense is rarely successful, however. Famous People with Pheochromocytoma President Dwight D. Eisenhower experienced several cardiovascular events, including a heart attack in 1955 and multiple strokes, alongside documented episodes of severe hypertension throughout his life. Despite extensive medical evaluation, the underlying cause of his erratic blood pressure remained undiagnosed until his death in 1969. Autopsy findings unexpectedly revealed a 1.5 cm pheochromocytoma in the left adrenal gland, suggesting that the tumor may have contributed to his hypertensive crises and potentially exacerbated his ischemic cardiomyopathy. ==Etymology==

1920s: from phaeochrome (another term for chromaffin), from Greek phaios 'dusky' + khrōma 'color', + -cyte. == References ==