Pheochromocytomais a rare tumor of theadrenal medullacomposed ofchromaffin cellsand is part of theparaganglioma(PGL) family of tumors, being defined as an intra-adrenal PGL.[2][4][5]These neuroendocrine tumors can be sympathetic, where they releasecatecholaminesinto the bloodstream which cause the most common symptoms, includinghypertension(high blood pressure),tachycardia(fast heart rate), sweating, and headaches.[6][7]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).[8]PGLs of the head and neck are typically parasympathetic and their sympathetic counterparts are predominantly located in the abdomen and pelvis, particularly concentrated at theorgan of Zuckerkandlat the bifurcation of the aorta.[9]
The symptoms of a sympathetic pheochromocytoma are related tosympathetic nervous systemhyperactivity.[10]The classic triad includesheadaches(likely related to elevated blood pressure, orhypertension),tachycardia/elevated heart rate, anddiaphoresis(excessive sweating, particularly at night, also known ashyperhidrosis).[7]However, patients are unlikely to experience continuous symptoms. Due to theparoxysmalnature of catecholamine synthesis and release, patients may experience "attacks" or "spells" where they are suddenly overwhelmed with signs and symptoms of their tumor.[11]Attacks can occur spontaneously (without warning) or may be triggered by a variety of pharmaceutical agents (includinghistamine,metoclopramide,glucagon[12]andadrenocorticotropic hormone), foods that containtyramine(cheese and wine), intraoperative tumor manipulation,intubation,or during anesthetic induction.[13]
Adrenal gland; themedulla(center, red) is the origin of the pheochromocytoma.There is an adrenal gland, highlighted in yellow, on top of each of the kidneys.
Other clinical manifestations that have been reported include (in no particular order):[6][13]
While the symptoms of a pheochromocytoma are quite common, the disease has been referred to as "the great mimic".[14]It is estimated that approximately 0.1% of patients with hypertension have a pheochromocytoma, and it is often misdiagnosed asessential hypertension.[7]As symptoms are oftenparoxysmal(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 forpre-menopausalrelatedhot flashes.Unmanaged pheochromocytoma is dangerous and can lead to serious, potentially fatal, complications, including stroke and hypertension-induced organ damage.[15][16]Thecardiovascularsystem is the most commonly involved.[17][18][19]
Inpregnancy,pheochromocytoma is associated with significantmaternalandfetal mortality,mainly due to hypertensive crisis in the mother and intrauterine growth restriction in the fetus.[20][21]
Misdiagnosis of pheochromocytoma can be deadly, asbeta-blockers,often perscribed for hypertension, can lead to unopposed Alpha in the context of pheochromocytoma.[22]Most mortality associated with diagnosed pheochromocytoma came from surgery and hypertensive crisis, but mortality has greatly improved.[23]
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.[18]The prevailing symptom is elevated systolic blood pressure (> 200 mmHg) that is unresponsive to traditional treatment regimens and threatensend-organ damage.[17]Patients require immediate, life-saving treatment to prevent further damage to other organs and/or death.
Myocardial Ischemia/Infarction:A heart attack is often caused by a significant build-up of plaque (atherosclerosis) in thecoronaryvessels. Patients with pheochromocytoma present with myocardial infarctions despite an overall lack of plaque build-up, indicating a different mechanism for the myocardial infarction. Current research hypothesizes that the tumor secretes massive amounts of catecholamines, which directly interact withmyocardial(heart) tissue and exert negative effects including oxygen deprivation, leading to acceleratedscarringand cell death.[17]
ToxicMyocarditis:Even in patients withoutmyocardialdamage, excessive catecholamines can result in abnormalSTchanges on anECG.Norepinephrine(a catecholamine) is hypothesized to result in damaged cardiac tissue by inhibiting coronary blood flow and depriving cells of oxygen, thus resulting inischemictissue.[19]Fortunately, following tumor excision and the subsequent quelling of catecholamines, the damage has been proven reversible.
Cardiomyopathy:Pheochromocytomas have been implicated in various types of cardiomyopathy, including (myocarditis, see above),dilated cardiomyopathy,and stress-induced orTakotsubo cardiomyopathy.[24]As with the other cardiovascular-related complications, excess catecholamines are responsible for the increased myocardial burden and significant physiologic stress.[25][non-primary source needed]Current literature indicates that most of the catecholamine-induced damage is reversible, thereby strengthening the argument for early and accurate diagnosis in order to allow for cardiac remodeling and prevent further destruction.[24][25]
Arrhythmias:Sinus tachycardiais the most common abnormal heart rhythm associated with a pheochromocytoma and is experienced by patients as the feeling of a "fluttering heart" orpalpitations.[17]Many othertachyarrhythmias(fast heart rate) have also been reported.
Headache:Headaches are one of the core clinical manifestations of a pheochromocytoma and can result in debilitating pain.[7]The majority of studied patients report their pain began and ended abruptly without warning and described the pain as a severe, bilateral throbbing (although the scale of severity was not published). While 71% of the studied patients reported headaches, just over 20% of the affected patients endorsed associatednausea,vomiting,photophobia,orphonophobia,which are typically associated withmigraines.[34][non-primary source needed]
Acute Renal Failure:Several reports have detailedrhabdomyolysis(rapid skeletal muscle breakdown) leading toacute kidney injuryand the need for transientdialysisin the undiagnosed pheochromocytoma patient as their primary presenting symptom.[35][36][37][38][non-primary source needed]Kidney failure is brought about by catecholamine-induced muscle injury. Norepinephrine causes vessels to narrow, thereby limiting blood flow and inducing ischemia.[35]
Multiple organ dysfunction syndrome(MODS)[39]: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.[40]Pheochromocytoma-related MODS is associated with multiple organ failure,hyperthermia> 40 degrees Celsius, neurologic manifestations, and cardiovascular instability resulting in either hypo or hypertension.[41]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.[42]
Current estimates predict that upwards of 40% of all pheochromocytomas are related to an inheritedgermlinesusceptibility mutation.[43]Of the remaining 60% of tumors, more than 30% are associated with asomatic mutation.[44]Given the high association with genetic inheritance, the United StatesEndocrine Societyrecommends that all patients diagnosed with a pheochromocytoma undergo an evaluation with a genetic counselor to considergenetic testing.[45]In the UK eligibility for NHS funded genetic testing is determined by criteria set by NHS England Genomics service.[46]The criteria in 2023 included all patients with paraganglioma and all patients with unilateral pheochromocytoma aged under 60.[47]The most recent data indicates that there are 25 pheochromocytoma susceptibility genes; however, just 12 are recognized as part of a well-known syndrome.[9]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.[48]There is no current consensus for how and whenasymptomatic 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.[49][non-primary source needed]
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.[50]
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 be upsetting to a child if their sibling was positive; an opportunity to ask questions and process results may be helpful.
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.[citation needed]
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.[7]
If a patient has the characteristic signs and symptoms of a pheochromocytoma and the decision is made to pursue additional biochemical (blood work) evaluation, thedifferential diagnosisis important as it is more likely to be somethingotherthan a pheochromocytoma given the relative frequency of 0.8 per 100,000 person-years.[3]
All patients with phaeochromocytomas are currently considered to have a lifelong risk of metastases and therefore conceptually they are all considered 'malignant'. 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[63]
Differential Diagnosis of Pheochromocytoma by System[a]
Elevated plasma freemetanephrinesis considered the gold standard diagnosis for pheochromocytoma.[64]Over 10 studies have confirmed that thesensitivityandspecificityof this test is 97% and 93% respectively; however, there is still concern forfalse positiveresults in the correct clinical scenario.[6]When interpreting a biochemical analysis for pheochromocytoma, the provider must pay close attention to the (1) conditions of the collection, (2)allmedications the patient is taking, and (3) their diet.[65]
Conditions of Collection:Unlike many routine laboratory tests that can be drawn at a moments 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 restingsupine(flat on their back) for 30 minutes before collection.[non-primary source needed][66][67]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.[65]
Pharmaceutical Interference:Many prescription,over-the-counter,and illicit substances can interfere with the proper collection of plasma metanephrines and lead to false-positive results. Providers should review a patient's medication list in-detail and have a discussion if temporarily discontinuing any of the interfering medications is possible. The most reported medications to result in falsely elevated metanephrines include:β-adrenoceptor blockers,phenoxybenzamine,tricyclic antidepressants,monoamine oxidase inhibitors,serotonin norepinephrine reuptake inhibitors (SNRI), andmethyldopa.[68][non-primary source needed][65]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.[68]After any possible prescription medications have been held, it is important to review any over-the-counter medications/supplements as well as the commonly usedacetaminophenandpseudoephedrinecause false elevations in metanephrine levels.[65][68]Finally, it is important to have open, non-judgemental discussions about the patient's recreational substance use.Amphetamines,nicotine,andcocainecan result in marked plasma norepinephrine levels.
Lifestyle and Diet:As with most lab work, the patient should refrain from eating (fasting) after midnight the night prior to their collection. However, there are further recommendations specific to a metanephrines collection, including abstaining from nicotine, alcohol, and exercise for at least 12 hours prior to their lab draw.[9]Patients should also avoid catecholamine-containing foods (fruits, fruit drinks, chocolate, caffeine, tomatoes, beans, nuts, and potatoes) for a minimum of 24 hours prior to collection.[7][69][70]
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.[45][71]
Twenty-four hour urinary metanephrines are an acceptable alternative if the plasma test is unavailable.[72]Other additional biomarkers can be helpful to aid in the diagnosis of pheochromocytoma as well, most notable isChromogranin 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.[73]However, a 2006 report from Italy found that over 90% of studied pheochromocytoma patients demonstrated elevated chromogranin A levels.[74]If metanephrine values are equivocal, chromogranin A can be used as an adjunct marker to predict the presence of a tumor.[citation needed]
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 remained the same, consider administering aclonidinesuppression test.[7][75]In the 1970s, the drug clonidine hydrocloride swept the market as a novel agent forhypertension;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.[76]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.[77][78][79]However, a one-time, weight-based dose can be utilized in limited settings to help determine disease status.[65]Afterfastingovernight, patient's will present to their testing site for a baseline metanephrines blood draw and clonidine administration. They will remainsupinefor (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.[65]It is important to note that if a patientdoes nothave a pheochromocytoma, they may become extremelyhypotensivefollowing 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.[non-primary source needed][80]Further research indicates that the biomarker is also a useful indicator ofmetastaticdisease – which is the only current biochemical evidence of metastases to date.[81]
While diagnostic, laboratory values can also provide physician's with important information about the type, location, size, and associated tumorgenotype.[71]There are (3) major, well-recognized biochemical phenotypes that can be used by health care providers to direct patient care.[82]
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[71]
More likely to indicate an extra-adrenal tumor[83]
Patients are more likely to present with continuous, persistent pheochromocytoma-related symptoms (hypertensionandtachycardia) compared to those that are classically episode with an adrenergic phenotype[71]
Structure of dopamineDopaminergic(Dopamineand 3-methoxytyramine)
More likely to indicate an extra-adrenal tumor of the head and neck[82]
Patients are more likely to be asymptomatic; however, they may present with non-specific signs ofnausea,vomiting,abdominal pain,diarrhea,and weight loss secondary to the stimulation of dopamine receptors throughout thegastrointestinal tract[71]
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.[83]
Anatomic imaging refers tocomputed tomography(CT) [CAT scan] ormagnetic 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.[84]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 anendocrinologistafter anincidental(unanticipated finding)adrenal noduleis found on a scan ordered for another reason.[85]For example, "Patient M" presents to his local emergency room for abdominal pain and a CT is ordered to rule-out appendicitis; however, theradiologistnotes there is a 3.5 centimeter right adrenal mass.[citation needed]
While there has not been aconsensuson 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 ionizingradiation,MR is preferred in children and pregnant women.[86]Furthermore, theintravenous contrastused in CT can causekidneydamage and should therefore be avoided in patients with pre-existing damage.[87]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.[88]When patients become anxious and begin to move in the machine, this causes motion artifact, which occurs less in CT-based images.[89]
Compared to CT and MR,ultrasoundis 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.[90]
The imaging modalities discussed below are for tumor characterization, confirmation ofmetastatic disease,and treatment planning – they are not used to discern tumor location or help the surgical team prepare for excision.[91]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.[86]Over the last decade, there have been five functional techniques used to evaluate the pheochromocytoma patient (1) 18F-fluorodeoxyglucosepositron emission tomography (18F-FDGPET), commonly referred to as the PET scan, (2) iodine-123meta-iodobenzylguanadine(123I-MIBG), (3) 18F-flurodihydroxyphenylalanine (18F-FDOPA),(4) 68Ga-DOTA coupled somatostatin analogs (68Ga-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.[citation needed]
MIBG Scintigraphy– 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 theabdomen.The darkened structure at the head of the patient is thethyroid gland,while the darkened structure in the pelvis of the patient is thebladder.This is normal physiologic uptake.
The first functional imaging technique utilized in pheochromocytoma patients was123I-MIBGscintigraphy.Given the compounds similar structure to the catecholaminenorepinephrine(secreted by pheochromocytomas), MIBG was well-suited for uptake by mostneuroendocrine tumors.[92]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.[93]However, further investigation revealed that while MIBG excelled with adrenal lesions, it was far less superior in patients with extra-adrenal paragangliomas, particularly with specificgenetic variantslike those in thesuccinate dehydrogenasesubunit–encoding genes (SDHx).[81]As thepositron emission tomographyscans were developed, MIBG has slowly lost its favor for the pheochromocytoma patient.[81]
FDGPET – the tumor is appreciated as the dark structure in the patient's left chest. Darkened structure at head of patient is the brain, posterior to the abdomen are the kidneys, in the pelvis is the bladder. These are normal.
Of the four above mentioned modalities,18F-FDGPETis the most common and readily available functional imaging technique at most hospital systems, but the least-specific toneuroendocrine 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.[81]
Following the development of FDG-PET, neuroendocrine-specific PET scans began to emerge. One of the first favorable imaging modalities was18F-FDOPA, which demonstrated a high sensitivity in detecting head and neck paragangliomas as well as non-metastatic disease outside of the head and neck.[81][94]Unfortunately, in cases ofmetastaticdisease, particularly related to succinate dehydrogenase subunit B (SDHB)mutations,18F-FDOPA fell inferior to the traditional FDG-PET.[95]However, for patients with genetic variants in other pheochromocytoma-susceptibility genes (NF1,VHL,RET)18F-FDOPA has become the preferred radiopharmaceutical agent.[96]
The newest PET modality involvessomatostatin receptortype two receptor imaging with68Ga-DOTA analogues.[89]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 withsuccinate dehydrogenase(SDHx) mutations.[non-primary source needed][97]While FDOPA inconsistently detected metastatic disease,68Ga-DOTA analogues have demonstrated superior localization of metastatic pheochromocytoma.[non-primary source needed][98]When directly compared in one head-to-head study in 2019,68Ga-DOTA analogues outperformed FDOPA, particularly in the detection of metastatic bone lesions.[99]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.[100]
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.[101]
Surgical resection is the only curative option for pheochromocytoma as of 2019.[102]A successful excision is amultidisciplinaryeffort involving theendocrinologistand the patientpre-operatively(discussed below) and the surgical team andanesthesiologistintraoperatively. Without frequent and adequate communication between all of the above-mentioned teams, a favorable outcome is much more difficult.[102]TheUnited States Endocrine Society2014 Clinical Practice Guideline for pheochromocytoma recommend alaparoscopicadrenalectomy(minimally invasive technique) for most adrenal tumors, unless they are invasive or are larger than 6.0 centimeters.[45]A 2018systematic reviewsuggests thatlaparoscopic retroperotenial adrenalectomyappears to reduce late morbidity, time to oral fluid or food intake and time to ambulation when compared to laparoscopic transperitoneal adrenalectomy, however there is uncertainty about these effects due to very low-quality evidence.[103]For outcomes such as all-cause mortality, early morbidity, socioeconomic effects, and operative and postoperative parameter, the evidence is uncertain about the effects of either interventions over the other.[103]
It is important to note that 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.[non-primary source needed][104][105]Anopenprocedure (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 withmalignantand/ormetastaticdisease, current research indicates a successful operation is feasible and results in a shorter hospital stay.[non-primary source needed][106]Literature within the last decade has also demonstrated that the robotic technique may be successfully utilized foradrenal tumors.[107]
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-longsteroid replacementif the left and right adrenal glands need to be removed.[108]The issue is particularly important in patients withMENandVHL-related disease, which has a higher chance of bilateral pheochromocytomas.[non-primary source needed][109]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.[108]
Arguably, the most important part of a pheochromocytoma surgical plan is an adequate pre-operative blockade. Excesscatecholamineshave been described as a dormant volcano, ready to erupt at any time, wreaking catastrophic havoc on the body.[110]While an eruption can occur at any time, two of the most common triggers areanesthesiaand direct tumor manipulation, making surgery one of the most dangerous times for a pheochromocytoma patient if not properly prepared.[non-primary source needed][111]In order to help circumvent a catecholamine-crisis, theUnited States Endocrine Societyrecommends that all patients with functional (hormonally active) tumors be started on a pre-operativeAlpha -adrenoceptorblockade a minimum of seven days prior to surgery.[45]There are several medication options depending on the clinical scenario, each with their own associated strengths and weaknesses.
If the patient's blood pressure is moderately elevated, a selective, short-acting Alpha -1 adrenoceptor antagonist (doxazosin,prazosin,terazosin) is the preferred agent.[110]However, the patient should be warned about the potential side-effect known as "thefirst-dose phenomenon."When patients are initially exposed to one of the above agents, they may becomelightheaded,dizzy,andnauseous,particularly when transferring from a seated to standing position due to a rapiddecrease in blood pressure.[112]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 uncontrolledhypertension,the non-selective Alpha -1 and 2 adrenoceptor antagonist (phenoxybenzamine) should be utilized.[110]Unfortunately, compared to the selective agents listed above, phenoxybenzamine is much more expensive and may not be readily available to some patients. Commonside effectsincludedry mouth,nasal congestion,andimpaired male ejaculation,all of which do not cease with time and may limit patientcompliance.[113]While uncommon, patients may have a hormonally-active pheochromocytoma and a normal blood pressure. One comparison from 2014 found that a small dose of acalcium-channel blocker(such asamlodipine) may be used pre-operatively in some people.[114]This will not drastically lower the patients blood pressure and make themhypotensive,but it will assist the surgical and anesthesia teams if there ishemodynamic instabilityduring the operation.
An elevated heart rate (tachycardia) and the feeling of a racing heart (palpitations) may follow after initiating anAlpha -adrenoceptor antagonist.If that is the case, abeta-adrenoceptor antagonistis then prescribed to control the heart rate.[110]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).[110]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.[needs update][115]
Beta-adrenoceptor antagonistsshould not be given alone in a pheochromocytoma patient – this can lead to severe consequences.[non-primary source needed][116]In 1995, a team of physicians from London described the death of a person who had been recently diagnosed pheochromocytoma after initiation ofpropranolol,a non-selectivebeta blocker.She quickly developed ahypertensive crisisleading toshock,myocardial infarction,heart failure,and dense righthemiplegia.Despite attempts at resuscitation, the person died several days later.[117]This complication is related to the impact that Alpha and beta-adrenoceptor antagonists have onblood vesselscombined with the actions ofcatecholamines.The normal blood vessel is open, allowing for adequate blood flow. When catecholamines activate the Alpha receptor, thevessel constricts(gets smaller), which results inhypertension.[118]However, when catecholamines active the beta receptor, theblood vessel dilates(gets larger) and allows for increased blood flow, reducing the blood pressure.[119]If a pheochromocytoma patient isonlystarted on a beta-adrenoceptor antagonist, this reverses the protectivevasodilationand worsens the patient's hypertension.
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 Alpha -blockade is necessary. In 2017, a team of researchers from Germany published anobservational case seriesthat called into question the current recommendations for Alpha -blockade.[120]The study examined the intraoperative maximal systolic arterial pressure in people with and withoutAlpha -adrenoceptor blockadeand found no difference in complications between the two groups.[120]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.[121]These articles resulted in rebuttals[111][122]from research teams in the United States, but an international consensus has not yet been reached.
Excess catecholamines cause a decrease in the totalblood volume,making a patient vulnerable tohypotensionduring the operation.[123]Therefore, a high-sodium diet with adequate fluid intake should be encouraged prior to surgery.[124]Some institutions in the United States will even admit patients the night prior to surgery forintravenousfluid replacementstarting at midnight until the time of the operation.[110]However, a small trial from 2009 reported no difference inmortalityin patients treated with preoperative intravenous fluids compared to those who did not.[125]
In a 2010 survey of 40 endocrinologists by researchers at theCedars-Sinai Medical Centerin Los Angeles, California, nearly all indicated the importance of preoperativevolume 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.[needs update][non-primary source needed][126]When the patients were stratified by age, those that were younger received the advice tohydrate,but older patients did not. It washypothesizedthat the providers chose to forego volume repletion in the older patient population for fear of their potentialcomorbidities(heart failure) where excess fluid is dangerous.[126]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.
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,andessential hypertensionmust also be considered. A perioperativehypertensive crisisis first treated with a 5.0 milligram (mg)intravenousbolusofphentolamine,with additional 5.0 mg dose every ten minutes until the blood pressure falls within an acceptable range.[non-primary source needed][129]If the blood pressure is only minimally elevated, the patient can resume their Alpha and beta-adrenoceptor antagonist from prior to surgery.[127]
Hypotension:There are several reasons a patient may have low blood pressure in the post-operative period. First and foremost, the tumor (and its abundance of catecholamines causing high blood pressure) has been removed. Furthermore, the patient may still experience the effects of theirAlpha -adrenoceptor antagonist,which causes lower blood pressure.[128]First-line treatment for postoperative hypotension is aggressivefluid resuscitation,which is why ensuring the patient is well-hydrated (see above) prior to surgery is so imperative.[127]Vasopressorsmay be needed if the blood pressure does not respond to fluids.
Hyperglycemia:Catecholamines prevent the secretion ofinsulin– a hormone responsible for lowering the body'sblood glucose(sugar). Blood glucose levels should be checked frequently in the perioperative period and insulin should be given as needed if levels are elevated. Following resection, tumor-related hyperglycemia is likely to resolve.
Adrenal Insufficiency:Following a bilateral adrenalectomy (left and right), the patient is no longer capable of secreting the necessaryhormonesto keep their body functioning. Life-long steroid (hydrocortisoneandfludrocortisone) oral supplementation may be required to ensure they do not develop adrenal insufficiency.[non-primary source needed][132]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 intraopertively to mimic the natural physiology of the adrenal glands.[133]The typical regimen when post-operative adrenal insufficiency is thought to be likely:[127][128]
Repeat administration of 25–50 mg intravenous hydrocortisone every eight hours for a maximum of 72 hours (3 days) after the operation. Convert to oral replacement therapy as soon as the patient is able to take medication by mouth
Patients should be transitioned to a normal maintenance (regular, daily) dose of steroids prior to discharge and referred to endocrinology for proper titration and management. Depending on the patient'stotal body surface area,the total typical daily dose of hydrocortisone is between 15 and 25 mg daily (divided into morning and afternoon pills).[134]
Those who have lost both their adrenal glands will also require another steroid (mineralcorticoidreplacement). The typical daily dose is between 50 and 200 micrograms offludrocortisone[134]
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.
Metastaticpheochromocytoma is defined as the presence of tumor cells (chromaffin tissue) where they are not normally found.[135]Patients with a paraganglioma are more likely to develop metastases than those with a pheochromocytoma.[136]The most common extra-adrenal sites of metastases are thelymph nodes,lung,liver,andbone.[137]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.[135]Of all the genetic variants,succinate dehydrogenase subunit B(SDHB)mutations have the highest rates of developing metastatic disease.[136]Another study has reported increasedmortalityassociated with male sex and synchronous metastases.[136]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.[138]
Laparoscopicapproach to the original disease, especially in big tumors, has been appointed as an important risk factor for tumoral seeding.[139]
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.[140]
Surgery– Normally, the goal of surgery is completecytoreductive surgery;[139]leave no remnant of disease.[141]However, with widespread metastatic disease, this is not always feasible. Therefore, a surgicaldebulkingprocedure 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 tochemoor radionuclide therapy, or simply decrease the size of the tumor.[142]Unfortunately, the intended relief from the procedure is often short-lived, especially if the patient has disease outside the abdomen.[142]A 2013 study from theNational Institutes of Healthreported 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.[142]
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.[143]This also aids surgical visualization and offers the best opportunity to identify and remove metastatic lymph nodes.[144]Reports have also indicated the utility of administering a radionuclide agent like iodine-123meta-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.[145]
Patient receiving radiation therapy to the region of the head and neck. Full facial mold is in place to protect areas where they do not want exposure.
Radiation Therapy– With regard to pheochromocytoma, radiation techniques are primarily used for pain control, specifically with regards tobone metastases,local control of the disease, and to limitspinal cord compression.[146]A multidisciplinary team from theMayo Clinicretrospectively reviewed all of their patients who underwentexternal beam radiation therapyfrom 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.[147]Another report from the same institution looked at almost two decades of patients who underwentradiofrequency ablation,cryoablation,orpercutaneous ethanol injectionfor 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 ofcatecholamineexcess.[148]
Chemotherapy– The most commonchemotherapyregimen for metastatic pheochromocytoma iscyclophosphamide,vincristine,anddacarbazine,collectively known as CVD.[149][150]Response to therapy is measured by a reduction in total tumor volume as well as symptomatic relief, reported by the patient. Asystematic reviewandmeta-analysisof 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.[149]While there was no difference inoverall survivalbetween 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.[151]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.[152]Genetic status has been shown to greatly impact response to CVD. A team of researchers from theNational Institutes of Healthreported that patient's withsuccinate dehydrogenase subunit B(SDHB)mutations are not only more likely to initially respond to CVD, but that they also experienced over 30 months ofprogression-free survival(time until tumor returned) with continued administration.[153]
However, CVD is not the only proven chemotherapeutic regimen in the pheochromocytoma patient. A 2018 report demonstrated the remarkable response of twoSDHBpatients who failed CVD chemotherapy (disease progressed despite medication), but were then treated withtemozolomide(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.[154]Several studies have since reported successful responses with TMZ, particularly in theSDHBsub-population.[155][156]
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.[157]Median overall survivalwas 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 were able to decrease their anti-hypertensive medications and reported symptomatic improvement.[157]There are several patients who are not eligible for MIBG treatment, including pregnant women (exposure to radiation is harmful to thefetus), women who are activelybreast feeding,patients inrenal failure,and those are who not expected to live longer than three months.[158]As MIBG therapy can destroy thethyroid,protective medications (potassium iodide) are started prior to treatment and need to be continued for at least three weeks after therapy concludes.[158]Associatedside effects(muscle weakness,nausea,vomitingandhematologic (blood) toxicities,are common, but often minimal, and can be mitigated with slow, steady dosing.[159]
Top:Purple lesions are metastatic disease detected with DOTATATE imaging.Bottom:Same patient. Purple lesions are metastatic disease detected with FDG PET
The newest of the treatment options, PRRT utilizes the 68-GaDOTAanalogues mentioned above in the functional imaging section.[160]Treatment with177Lu-DOTATATEfirst demonstrated success in patients with undifferentiated neuroendocrine tumors and then trials began with metastatic pheochromocytoma patients.[161][162]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.[163]Overall toxicity was low, with no high-grade haematological (blood) or kidney damage reported.[163]At the end of that same year, a systemic review looked at all published articles (12) where metastatic pheochromocytoma patients underwent PRRT and found that treatment-relatedadverse eventsare minimal, with only 5 out of 102 patients choosing to voluntarily initiate treatment discontinuation.[164]Newer reports have detailed the utility of combining90Y-DOTATATE with the traditionally studied177Lu analog and the various possibilities and novel treatment options these combinations will bring to the field.[100]While the overall reported side-effects have been promising, it is important to note that a collaborative effort between theNational Institutes of HealthandRadboud University Medical Centrereported two unfortunate cases of rapid disease progression following a remarkable, almost complete response to PRRT. While the etiology of their recurrence is unknown, the team speculated that an elevated tumor marker (Ki-67) could be an indication of a poor response to PRRT and called for pre-PRRT assessments to include Ki-67 values to help individualize patient treatment plans.[165]
According to theNational Cancer Institute,prognosisis defined as the likely outcome of a disease OR, the chance of recovery or a recurrence.[166]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.[167]An article about prognosis published in 2000 reported a 91% 5-year survival rate in their patient population; however, over 86% of their patients hadsporadic tumors(no known genetic mutation), which commonly have low malignant potential.[168]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 amedian survivalof 6.7 years.[169]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.[169]
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.[170]The actual location of the metastases can also indicate prognosis, withosseouslesions (bone) faring better than their soft-tissue (lung,liver) counterparts.[171]
According to the North American Neuroendocrine Tumor Society, theprevalenceof 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.[172]In the United States, this equates to an annualincidence(new cases per year) of 500 to 1,600 cases.[172]However, approximations in the early 2000s reported that upwards of 50% of pheochromocytoma diagnoses are atautopsy;therefore, the above estimations may be lower than expected.[13]In a 50-year autopsy case series, theMayo Clinicreviewed 54 pheochromocytoma cases between 1928–1977 and discovered that just 24% of the patients were correctly diagnosed prior to their death.[needs update][non-primary source needed][173]Outside of the United States, several countries have documented their own epidemiological studies and compared them to what is known inNorth America.In the first national, epidemiological population-based study inAsiautilizingKoreanNational 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.[174]This is lower than the occurrence reported fromRochester, Minnesota(0.8 per 100,000 person-years), in a study conducted from 1950 to 1979.[3]However, theNetherlandsalso conducted a study using a nationwide registry and reported incidence results of 0.57 per 100,000 person-years from 2011 to 2015, which was a significant increase from their 0.37 cases per 100,000 person-years reported from 1995 to 1999.[175]Currenthypothesesfor why the incidence of pheochromocytoma is growing in theDutchpopulation point to the advent of modern imaging evaluation and the ability to detect these tumors prior to death.[176]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.[177]When younger patients are diagnosed with a pheochromocytoma, there should be a high suspicion for hereditary disease, asgenetic anticipation(earlier disease onset with each generation) is associated with some mutations.[178]
Likelihood of diagnosis when an adrenal-nodule is identified; pheochromocytoma is in yellow near the top-right corner.
Classically, the pheochromocytoma "rules of 10" have been taught, particularly to medical students:[179]
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.[177]
As suggested above,incidentalimaging 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 oncomputed tomographyormagnetic resonanceimaging, there is a 5–10% chance the lesion is a pheochromocytoma.[177]The incidence of adrenal tumors is found in the infographic above, with pheochromocytoma noted in yellow in the top right corner.
Professor Ludwig Pick, the German physician who first coined the term "pheochromocytoma" in 1912 after recognizing the color-change associated with the addition of chromium salts
In 1800, anIrishphysician (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 hecticflushdistinctly marked on each cheek "with a" constant profuse and universalperspiration."[180]Following his death, a group of physicians performed anautopsyto determinecause of deathand 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).[180]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 theGermanFelix Fraenkel, who provided a clinical and morphologic picture of this tumor.[181][182]While various physicians were recognizing symptoms and treating patients,CzechbiologistAlfred Kohnreported his discovery of theparagangliasystem, 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 theadrenal gland.[183]
In 1908, twopathologists,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.[184]Just four years later, German pathologistLudwig Pickcoined the term "pheochromocytoma" after he observed the consistent color change in tumors associated with theadrenal medulla.[185]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 theMayo Clinic) became the first physician to successfully excise a pheochromocytoma.[185]However, Mayo was likely unaware of the diagnosis prior to the operation. Not until 1929 was a pheochromocytoma recognized preoperatively.[13]Throughout the early 1900s, the operativemortality ratefor 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.[186]From this point forward, physician-scientists have been recognizing patterns in patients with pheochromocytoma and identifying genetic associations and various syndromes.[13]
While a rare disease, there have been several references to pheochromocytoma in popular culture and the media, specifically medicaltelevision dramas.Additionally, there is a strong online patientadvocacy communitythat works to connect patients with rare diseases and allows them to meet other individuals who are experiencing similar diagnoses and treatment strategies.
The zebra has become a powerful symbol in the pheochromocytoma advocacy community and represents the rare medical cases that are more likely to be misdiagnosed.
In the medical community, students are often taught "when you hear hoofbeats, think horses, not zebras."[187]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 thezebrahas 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.[188]
TheNational Organization for Rare Disordersis a United States–based advocacy parent organization with the goal of promoting awareness and research opportunities to cure rare diseases.[189]Groups such as these encourage patients to become their own advocates and change agents in their healthcare decision-making processes.
In July 2012, an actual pheochromocytoma patient, Tannis Brown, former vice-president of the PheoPara Troopers, was featured on theDiscovery Fit & HealthNetwork programDiagnosis: Dead or Alive.[190]The show highlighted her personal struggle with misdiagnosed disease as many physicians felt her episodic headaches andhypertension(high blood pressure) were related to stress.[191]
In the seventh and eighth seasons ofGrey's Anatomy,series regular Henry has aVon Hippel-Lindau(VHL)mutation that has resulted in a pheochromocytoma. Thestory arcwas met with mixed opinions from the rare disease community.[192]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.[193][194]
A case of pheochromocytoma was featured in thefirst episode of season 2ofHouse MD.Dr. Houseand 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 oflegal defenseis rarely successful, however.
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