Pheochromocytoma
Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred to as a paraganglioma. These neuroendocrine tumors are capable of producing and releasing massive amounts of catecholamines, metanephrines, or methoxytyramine, which result in the most common symptoms, including hypertension (high blood pressure), tachycardia (fast heart rate), and diaphoresis (sweating). However, not all of these tumors will secrete catecholamines. Those that do not are referred to as biochemically silent, and are  predominantly located in the head and neck. While patients with biochemically silent disease will not suffer from the typical disease manifestations described above, the tumors grow and compress the surrounding structures of the head and neck, and can result in pulsatile tinnitus (ringing of the ear), hearing loss, aural fullness, dyspnea (difficulty breathing), and hoarseness. While tumors of the head and neck are parasympathetic, their sympathetic counterparts are predominantly located in the abdomen and pelvis, particularly concentrated at the organ of Zuckerkandl. Signs and symptoms. The signs and symptoms of a pheochromocytoma are those related to sympathetic nervous system hyperactivity . The classic triad includes headaches (likely related to elevated blood pressure, or hypertension), tachycardia/elevated heart rate, and diaphoresis (excessive sweating, particularly at night, also known as hyperhidrosis). However, patients are unlikely to experience continuous symptoms. Due to the paroxysmal nature of catecholamine synthesis and release, patients may experience "attacks" or "spells" where they are suddenly overwhelmed with signs and symptoms of their tumor. Attacks can occur spontaneously (without warning) or may be triggered by a variety of pharmaceutical agents, foods, intraoperative tumor manipulation, intubation, or during anesthetic induction. While the above symptoms are classic, other common clinical manifestations have  been reported and include (in no particular order) Complications. While the symptoms of a pheochromocytoma are quite common, the disease has been referred to as "the great mimic". Literature reports that just 0.1% of patients with hypertension are diagnosed with this rare endocrine disorder and symptomatic patients are often mistaken for much more common diseases. As symptoms are often paroxysmal (episodic/sporadic), patients may not immediately seek treatment as the problem "disappears on its own." Furthermore, when pictured in the ideal clinical scenario (an older woman in her mid-50s), the spontaneous attacks of flushing, sweating, and a racing heart may  be mistaken for pre-menopausal related hot-flashes. Unmanaged pheochromocytoma is dangerous and can lead to serious complications, including death. 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. Multiple organ dysfunction syndrome (MODS): 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. The most recent data indicates that there are 25 pheochromocytoma susceptibility genes; however, just 12 are recognized as part of a well-known syndrome. Determining the genetic status of a pheochromocytoma patient is crucial – each gene is inherited in a different pattern, associated with specific disease characteristics, and may respond more favorably to certain treatment options. Furthermore, early identification can guide physicians on screening recommendations for first degree relatives of patients with pheochromocytoma. 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 at an individual level with the patient and their provider to develop a personalized screening plan that alternates 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. 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) MAX (MYC Associated Factor X); TMEM127 (Transmembrane Protein 127) Other gene variants. There have been several published case reports of other, rare pheochromocytoma-associated susceptibility genes: Several additional gene variants have been described, but the provided information is inconsistent and a consensus has not been reached in the community if these mutations are truly pheochromocytoma susceptibility genes. Diagnosis. Differential. If a patient 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. 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. When interpreting a biochemical analysis for pheochromocytoma, the provider must pay close attention to the (1) conditions of the collection, (2) "all" medications the patient is taking , and (3) their diet. 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. Alternative tests. Twenty-four hour urinary metanephrines are an acceptable alternative if the plasma test is unavailable. 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 can not be discontinued or repeated labs remained 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. After fasting overnight, patient's will present to their testing site for a baseline metanephrines blood draw and clonidine administration. They will remain supine 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 hypotensive 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 metastatic disease - which is the only current biochemical evidence of metastases to date. Biochemical phenotypes. While diagnostic, laboratory values  can also provide physician's with important information about the type, location, size, and associated tumor genotype. There are (3) major, well-recognized biochemical phenotypes that can be used by health care providers to direct patient care. Across both an adrenergic and a noradrenergic phenotype, the greater the sum of plasma or urinary concentrations of metanephrine and normetanephrine, the larger the expected tumor diameter. Tumor localization. Anatomic imaging. Anatomic imaging refers to computed tomography (CT) [CAT scan] or magnetic resonance imaging (MR) scans. These imaging modalities serve to initially locate the tumor and provide detailed information about size, morphology, and  structural relation to adjacent internal structures. 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. For example, "Patient M" presents to his local emergency room for abdominal pain and a CT is ordered to rule-out appendicitis; however, the radiologist notes there is  a 3.5 centimeter right adrenal mass. While there has not been a consensus on if 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 intravenous contrast 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 of time (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 avoid 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. 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 (F-FDG PET), commonly referred to as the PET scan, (2) iodine-123 meta-iodobenzylguanadine (I-MIBG), (3) 18F-flurodihydroxyphenylalanine (F-FDOPA),(4) 68Ga-DOTA coupled somatostatin analogs (Ga-DOTA),(5) 11C-Hydroxy ephedrine(HED-PET). From this point forward, these imaging modalities will be referred to in their abbreviated names found in parentheses. The first functional imaging technique utilized in pheochromocytoma patients was I-MIBG scintigraphy (Image Right). Given the compounds 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 suffering from 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 succinate dehydrogenase subunit X ("SDHx)." As the positron emission tomography scans were developed, MIBG has slowly loss its favor for the pheochromocytoma patient. Of the four above  mentioned modalities, F-FDG 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 F -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 metastatic disease, particularly related to succinate dehydrogenase subunit B ("SDHB)" mutations, F-FDOPA fell inferior to the traditional FDG-PET. However, for patients with genetic variants in other pheochromocytoma-susceptibility genes ("NF1, VHL, RET)" F-FDOPA has become the preferred radiopharmaceutical agent. The newest PET modality involves somatostatin receptor type two receptor imaging with Ga-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, Ga-DOTA analogues have demonstrated superior localization of metastatic pheochromocytoma. When directly compared in one head-to-head study in 2019, Ga-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 has shown to be an accurate tool to diagnose  and rule out pheochromocytoma in complex clinical scenarios and to characterise equivocal adrenal tumours. Management. 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. The United States Endocrine Society 2014 Clinical Practice Guideline for pheochromocytoma recommend a laparoscopic adrenalectomy (minimally invasive technique) for most adrenal tumors, unless they are invasive or are larger  than 6.0 centimeters. It is important to note that larger tumors can be attempted with a minimally invasive approach, but the team should be prepared to convert to an open procedure if necessary. 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 life-long 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. Pre-operative management. Arguably, the most important part of a pheochromocytoma surgical plan is an adequate pre-operative blockade. Excess catecholamines have been described as a dormant volcano, ready to erupt at any time, wreaking catastrophic havoc on the body. 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. In order 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 prior to surgery. There are several medication options depending on the clinical scenario, each with their 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. However, the patient should be warned about the potential side-effect known as "the first-dose phenomenon." When patients are initially exposed to one of  the above agents, they may become lightheaded, dizzy, and nauseous, particularly when transferring from a seated to standing position due to a rapid decrease in blood pressure. 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 patient's with uncontrolled hypertension, the non-selective alpha-1 and 2 adrenoceptor antagonist (phenoxybenzamine) should be utilized. Unfortunately, compared to the selective agents listed above, phenoxybenzamine is much more expensive and may not be readily available to some patients. Common side-effects include dry  mouth, nasal congestion, and impaired male ejaculation, all of which do not cease with time and may limit patient compliance. 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 patients 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. Just as with the alpha antagonists, there are selective (beta-1) and non-selective (beta-1 and beta-2) adrenoceptor antagonists. The selective agents (atenolol, metoprolol) are preferred to the non-selective agents (propranolol). There are several (labetalol, carvedilol) combined alpha-beta-adrenoceptor antagonists. These agents should be avoided whenever possible as there is upwards of seven times more beta-adrenoceptor antagonism than alpha, which can worsen hypertension and lead to a catecholamine crisis . 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 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 active 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 patients 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 if a blockade is necessary. In 2017, a team of researchers from Germany published an observational case series that called into question the current recommendations for a 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. The following year, a group from France published a similar article with a warning against waiting an entire week to begin alpha-blockade. The French researchers called for immediate surgical intervention and consideration of steps to mitigate any intraoperative catecholamine crisis. 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. However, a small trial from 2009 reported no difference in mortality in patients treated with preoperative intravenous  fluids compared to those who did not. 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 prior to 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. 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, comorbidities, and ability to self-hydrate. Post-operative management. The most common post-operative complications, likely causes, and treatment options are: "Cardiovascular" "Endocrine" There have been many other reported complications (renal failure, heart failure, intestinal pseudo-obstuction) 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. Of all the genetic variants, succinate  dehydrogenase subunit B "(SDHB)" mutations have the highest rates of developing metastatic disease. Another study has reported increased mortality associated with male sex and synchronous metastases. Metastases are divided into synchronous and metachronous; those that are synchronous have developed within several months of the primary tumor, while metachronous metastases do not appear for a significant period of time. Laparoscopic approach to the original disease, especially in big tumors, has been appointed as an important risk factor for tumoral seeding. Despite all of the below 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; 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) in order 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. A 2013 study from the National Institutes of Health reported that a majority of patients suffered from 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 in order 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 (I-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 1973-2015 and reported that 94% of patients acknowledged symptomatic improvement and over 80% of patients showed no evidence of recurrent disease 5-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 overall survival 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 patient's 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. "Radionuclide  Therapy" 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 pheochromcytoma, 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, it is important to note that 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. 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 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 1:2500 and 1:6500, 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 1600 cases . However, approximations in the early 2000s reported that upwards of 50% of pheochromocytoma diagnoses are at autopsy; therefore, the above estimations may be lower than expected. In a 50-year autopsy case series, the Mayo Clinic reviewed 54 pheochromocytoma cases between 1928–1977 and discovered that just 24% of the patients were correctly diagnosed prior to their death. 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 1950-1979. However, the Netherlands also conducted a study using a nationwide registry and reported incidence results of 0.57 per 100,000 person-years from 2011–2015, which was a significant increase from their 0.37 cases per 100,000 person-years reported from 1995–1999. 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 prior to 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: 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 between 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 between a 5 and 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. 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 suffered from 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). This would become the first known  clinical description of a pheochromocytoma, but as no features of the tumor itself were described, complete credit is given to the German Felix Fraenkel, who provided a clinical and morphologic picture of this tumor. 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. However, Mayo was likely unaware of the diagnosis prior to the operation. Not until 1929 was a pheochromocytoma recognized preoperatively . Throughout the early 1900s, the operative mortality rate for a pheochromocytoma ranged from 30-45%. 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. 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 in Texas, 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 with the goal of promoting awareness and research opportunities to cure rare diseases. Groups such as these encourage patients to become their own 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 "Greys 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. Then 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  actually 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 MD". 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.