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Pheochromocytoma

Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they release catecholamines into the bloodstream which cause the most common symptoms, including hypertension (high blood pressure), tachycardia (fast heart rate), sweating, and headaches. Some PGLs may secrete little to no catecholamines, or only secrete paroxysmally (episodically), and other than secretions, PGLs can still become clinically relevant through other secretions or mass effect (most common with head and neck PGL). PGLs of the head and neck are typically parasympathetic and their sympathetic counterparts are predominantly located in the abdomen and pelvis, particularly concentrated at the organ of Zuckerkandl at the bifurcation of the aorta.

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

Signs and symptoms
The symptoms of a sympathetic pheochromocytoma are related to sympathetic nervous system hyperactivity. The classic triad includes headaches (likely related to elevated blood pressure, or hypertension), tachycardia/elevated heart rate, and 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 (including histamine, metoclopramide, glucagon and adrenocorticotropic hormone), foods that contain tyramine (cheese and wine), intraoperative tumor manipulation, intubation, or during anesthetic induction. Other clinical manifestations that have been reported include (in no particular order):
 * Pallor
 * Heat intolerance
 * Weight loss
 * Chest and/or abdominal discomfort
 * Palpitations
 * Nausea/vomiting
 * Constipation
 * Orthostatic hypotension – becoming light-headed or dizzy after swiftly changing positions
 * Psychiatric manifestations
 * Anxiety, panic attacks, nervousness, tremors
 * Hyperglycemia (high blood sugar)

Complications
While the symptoms of a pheochromocytoma are quite common, the disease has been referred to as "the great mimic". It is estimated that approximately 0.1% of patients with hypertension have a pheochromocytoma, and it is often misdiagnosed as essential hypertension. 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, potentially fatal, complications, including stroke and hypertension-induced organ damage. The cardiovascular system is the most commonly involved.

In pregnancy, pheochromocytoma is associated with significant maternal and fetal mortality, mainly due to hypertensive crisis in the mother and intrauterine growth restriction in the fetus.

Misdiagnosis of pheochromocytoma can be deadly, as beta-blockers, often perscribed for hypertension, can lead to unopposed alpha in the context of pheochromocytoma. Most mortality associated with diagnosed pheochromocytoma came from surgery and hypertensive crisis, but mortality has greatly improved.

Cardiovascular system

 * 1) 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. The prevailing symptom is elevated systolic blood pressure (> 200 mmHg) that is unresponsive to traditional treatment regimens and threatens end-organ damage. Patients require immediate, life-saving treatment to prevent further damage to other organs and/or death.
 * 2) Myocardial Ischemia/Infarction: A heart attack is often caused by a significant build-up of plaque (atherosclerosis) in the coronary vessels. 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 with myocardial (heart) tissue and exert negative effects including oxygen deprivation, leading to accelerated scarring and cell death.
 * 3) Toxic Myocarditis: Even in patients without myocardial damage, excessive catecholamines can result in abnormal ST changes on an ECG. Norepinephrine (a catecholamine) is hypothesized to result in damaged cardiac tissue by inhibiting coronary blood flow and depriving cells of oxygen, thus resulting in ischemic tissue. Fortunately, following tumor excision and the subsequent quelling of catecholamines, the damage has been proven reversible.
 * 4) Cardiomyopathy: Pheochromocytomas have been implicated in various types of cardiomyopathy, including (myocarditis, see above), dilated cardiomyopathy, and stress-induced or Takotsubo cardiomyopathy. As with the other cardiovascular-related complications, excess catecholamines are responsible for the increased myocardial burden and significant physiologic stress.  Current literature indicates that most of the catecholamine-induced damage is reversible, thereby strengthening the argument for early and accurate diagnosis in order to allow for cardiac remodeling and prevent further destruction.
 * 5) Arrhythmias: Sinus tachycardia is the most common abnormal heart rhythm associated with a pheochromocytoma and is experienced by patients as the feeling of a "fluttering heart" or palpitations. Many other tachyarrhythmias (fast heart rate) have also been reported.

Nervous system

 * 1) Cerebrovascular Accident (Stroke): Multiple reports have detailed transient ischemic attacks or strokes in patients with a pheochromocytoma.        In a study of 130 patients with pheochromocytoma, 7 patients were diagnosed with a transient ischemic attack (the neurologic deficit completely resolved) and 3 patients experienced a stroke with persistent symptoms.
 * 2) Headache: Headaches are one of the core clinical manifestations of a pheochromocytoma and can result in debilitating pain. 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 associated nausea, vomiting, photophobia, or phonophobia, which are typically associated with migraines.

Urinary system
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.
 * 1) Acute Renal Failure: Several reports have detailed rhabdomyolysis (rapid skeletal muscle breakdown) leading to acute kidney injury and the need for transient dialysis in the undiagnosed pheochromocytoma patient as their primary presenting symptom.    Kidney failure is brought about by catecholamine-induced muscle injury. Norepinephrine causes vessels to narrow, thereby limiting blood flow and inducing ischemia.

Genetics
Current estimates predict that upwards of 40% of all pheochromocytomas are related to an inherited germline susceptibility mutation. Of the remaining 60% of tumors, more than 30% are associated with a somatic mutation. Given the high association with genetic inheritance, the United States Endocrine Society recommends that all patients diagnosed with a pheochromocytoma undergo an evaluation with a genetic counselor to consider genetic testing. In the UK eligibility for NHS funded genetic testing is determined by criteria set by NHS England Genomics service. The criteria in 2023 included all patients with paraganglioma and all patients with unilateral pheochromocytoma aged under 60. The most recent data indicates that there are 25 pheochromocytoma susceptibility genes; however, just 12 are recognized as part of a well-known syndrome. 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.
 * 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.

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.
 * 1) Pacak–Zhuang Syndrome
 * 2) * Hypoxia-inducible factor 2 alpha (HIF2A)
 * 3) * Polycythemia
 * 4) * Duodenal somatostatinoma
 * 5) * Retinal and choroidal vascular changes
 * 6) * Paraganglioma/Pheochromocytoma
 * 7) Pheochromocytoma and Giant Cell Tumor of Bone
 * 8) * H3 histone, family 3A (H3F3A), post-zygotic G34W
 * 9) * Pheochromocytoma/Paraganglioma
 * 10) Carney Triad
 * 11) * Gastrointestinal stromal tumor
 * 12) * Pulmonary chondroma
 * 13) * Paraganglioma
 * 14) Carney-Stratakis Syndrome
 * 15) * Gastrointestinal stromal tumor
 * 16) * Paraganglioma

Differential
The typical primary symptom is hypertension, which may be either episodic or continual. A diagnosis of pheochromocytoma should be suspected when the patient simultaneously presents with hypertension and the classic triad of heart palpitations, headaches, and profuse sweating.

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.

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

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.
 * 1) 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 resting supine (flat on their back) for 30 minutes before collection.  Specific supine reference values should be used in this scenario. Ensuring these conditions is difficult and may be cost-prohibitive at most institutions. In these cases, a rested, supine draw can be repeated following a positive result in a seated position to eliminate false-positive results.
 * 2) 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), and methyldopa.  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. After any possible prescription medications have been held, it is important to review any over-the-counter medications/supplements as well as the commonly used acetaminophen and pseudoephedrine cause false elevations in metanephrine levels.  Finally, it is important to have open, non-judgemental discussions about the patient's recreational substance use. Amphetamines, nicotine, and cocaine can result in marked plasma norepinephrine levels.
 * 3) 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. 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.

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 cannot 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.
 * 1) Adrenergic (Epinephrine and metanephrine)
 * 2) * More likely to indicate an adrenal tumor
 * 3) * 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
 * 4) * Patients are more likely to present with the classic, paroxysmal (episodic) symptoms described above
 * 5) Norepinephrine structure.svgNoradrengeric (Norepinephrine and normetanephrine)
 * 6) * More likely to indicate an extra-adrenal tumor
 * 7) * Patients are more likely to present with continuous, persistent pheochromocytoma-related symptoms (hypertension and tachycardia) compared to those that are classically episode with an adrenergic phenotype
 * 8) * Common in patients with von-Hippel Lindau and succinate dehydrogenase subunit X genetic variants
 * 9) Dopamine.svgDopaminergic (Dopamine and 3-methoxytyramine)
 * 10) * More likely to indicate an extra-adrenal tumor of the head and neck
 * 11) * Patients are more likely to be asymptomatic; however, they may present with non-specific signs of nausea, vomiting, abdominal pain, diarrhea, and weight loss secondary to the stimulation of dopamine receptors throughout the gastrointestinal tract
 * 12) * Particularly prevalent in patients with succinate dehydrogenase subunit B genetic variants

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 (18F-FDG PET), commonly referred to as the PET scan, (2) iodine-123 meta-iodobenzylguanadine (123I-MIBG), (3) 18F-flurodihydroxyphenylalanine (18F-FDOPA),(4) 68Ga-DOTA coupled somatostatin analogs (68Ga-DOTA),(5) 11C-Hydroxy ephedrine(HED-PET). 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 123I-MIBG scintigraphy. 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 with widespread metastatic disease. However, further investigation revealed that while MIBG excelled with adrenal lesions, it was far less superior in patients with extra-adrenal paragangliomas, particularly with specific genetic variants like those in the succinate dehydrogenase subunit–encoding genes (SDHx). As the positron emission tomography scans were developed, MIBG has slowly lost its favor for the pheochromocytoma patient.

Of the four above mentioned modalities, 18F-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 18F-FDOPA, which demonstrated a high sensitivity in detecting head and neck paragangliomas as well as non-metastatic disease outside of the head and neck. Unfortunately, in cases of metastatic disease, particularly related to succinate dehydrogenase subunit B (SDHB) mutations, 18F-FDOPA fell inferior to the traditional FDG-PET. However, for patients with genetic variants in other pheochromocytoma-susceptibility genes (NF1, VHL, RET) 18F-FDOPA has become the preferred radiopharmaceutical agent.

The newest PET modality involves somatostatin receptor type two receptor imaging with 68Ga-DOTA analogues. Over the last decade, further research continues to indicate the superiority of this functional imaging modality in a wide range of clinical scenarios, even surpassing anatomic imaging (CT/MR) in pediatric patients with succinate dehydrogenase (SDHx) mutations. While FDOPA inconsistently detected metastatic disease, 68Ga-DOTA analogues have demonstrated superior localization of metastatic pheochromocytoma. When directly compared in one head-to-head study in 2019, 68Ga-DOTA analogues outperformed FDOPA, particularly in the detection of metastatic bone lesions. An additional benefit of the DOTA analogues is the ability for treatment with peptide receptor radionuclide therapy, which will be discussed in the treatment section below.

Also, HED-PET has shown to be an accurate tool to diagnose and rule out pheochromocytoma in complex clinical scenarios and to characterise equivocal adrenal tumours.

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. A 2018 systematic review suggests that laparoscopic retroperotenial adrenalectomy appears 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. 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.

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. 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 patient's hypertension.

Controversy
While the pre-operative alpha and beta blockade discussed above is overwhelmingly recognized as the standard of care, particularly in the United States, there has been discussion at the international level if alpha-blockade is necessary. In 2017, a team of researchers from Germany published an observational case series that called into question the current recommendations for alpha-blockade. The study examined the intraoperative maximal systolic arterial pressure in people with and without alpha-adrenoceptor blockade and found no difference in complications between the two groups. 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

 * 1) Hypertension: In the pheochromocytoma patient, postoperative hypertension could indicate incomplete tumor resection or another tumor of unknown location. However, the traditional, non-specific causes of postoperative hypertension including pain, fluid overload, and essential hypertension must also be considered. A perioperative hypertensive crisis is first treated with a 5.0 milligram (mg) intravenous bolus of phentolamine, with additional 5.0 mg dose every ten minutes until the blood pressure falls within an acceptable range. If the blood pressure is only minimally elevated, the patient can resume their alpha and beta-adrenoceptor antagonist from prior to surgery.
 * 2) 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 their alpha-adrenoceptor antagonist, which causes lower blood pressure. First-line treatment for postoperative hypotension is aggressive fluid resuscitation, which is why ensuring the patient is well-hydrated (see above) prior to surgery is so imperative. Vasopressors may be needed if the blood pressure does not respond to fluids.

Endocrine

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.
 * 1) Hyperglycemia: Catecholamines prevent the secretion of insulin – a hormone responsible for lowering the body's blood 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.
 * 2) Hypoglycemia: After the tumor is removed, insulin is no longer inhibited, which can bring the blood glucose dangerously low. Symptoms include tremor, anxiety, palpitations, sweating, altered mental status (confusion), dizziness, and blurred vision. A retrospective analysis of beta blocker found that some beta blocker use may cause people to more prone to hypoglycemia and not experience these symptoms, which could delay the diagnosis.
 * 3) Adrenal Insufficiency: Following a bilateral adrenalectomy (left and right), the patient is no longer capable of secreting the necessary hormones to keep their body functioning. Life-long steroid (hydrocortisone and fludrocortisone) oral supplementation may be required to ensure they do not develop adrenal insufficiency. When the body is stressed (during surgery), the adrenal glands naturally produce more steroids; however, if the glands have been removed, they are unable to do so. Therefore, "stress-dosing" steroids are required and should be started intraopertively to mimic the natural physiology of the adrenal glands. The typical regimen when post-operative adrenal insufficiency is thought to be likely:
 * 4) 50 milligram (mg) intravenous hydrocortisone in the operating room prior to anesthesia
 * 5) 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
 * 6) 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's total body surface area, the total typical daily dose of hydrocortisone is between 15 and 25 mg daily (divided into morning and afternoon pills).
 * 7) Those who have lost both their adrenal glands will also require another steroid (mineralcorticoid replacement). The typical daily dose is between 50 and 200 micrograms of fludrocortisone

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 with recurrent biochemical evidence of disease within one year of the operation and less than 30% continued to be biochemically free of disease after five years.

In contrast to an operation for non-metastatic disease, an open procedure may be preferred over a minimally invasive technique 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 (123I-MIBG) prior to surgery and then scanning the patient intraoperatively with a probe to detect disease that may be missed with the naked eye. Radiation Therapy – With regard to pheochromocytoma, radiation techniques are primarily used for pain control, specifically with regards to bone metastases, local control of the disease, and to limit spinal cord compression. A multidisciplinary team from the Mayo Clinic retrospectively reviewed all of their patients who underwent external beam radiation therapy from 1973 to 2015 and reported that 94% of patients acknowledged symptomatic improvement and over 80% of patients showed no evidence of recurrent disease five years post-therapy. Another report from the same institution looked at almost two decades of patients who underwent radiofrequency ablation, cryoablation, or percutaneous ethanol injection for metastatic pheochromocytoma and reported that local control was achieved in over 85% of targeted lesions and that 92% of procedures were associated with reduced pain and/or symptoms of catecholamine excess.

Chemotherapy – The most common chemotherapy regimen for metastatic pheochromocytoma is cyclophosphamide, vincristine, and dacarbazine, collectively known as CVD. Response to therapy is measured by a reduction in total tumor volume as well as symptomatic relief, reported by the patient. A systematic review and meta-analysis of unstratified pheochromocytoma patients who underwent CVD therapy showed that 37% of patients had a significant reduction in tumor volume, while 40% of patients experienced lower catecholamine burden. 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
 * Iodine-131 meta-iodobenzylguanadine (MIBG)
 * As was mentioned in the functional imaging section above, MIBG is not only useful in locating the presence of metastatic disease, but also as an available treatment modality. In 2019, a multi-center phase 2 trial looked at the safety and efficacy of MIBG therapy in metastatic or unresectable (not conducive to surgery) pheochromocytoma patients and the results were promising. Median overall survival was 36.7 months and 92% of patients had at least a partial positive response (tumor shrinkage) or stable disease without progression within the first year of the study. Furthermore, over a fourth of the patients were able to decrease their anti-hypertensive medications and reported symptomatic improvement. There are several patients who are not eligible for MIBG treatment, including pregnant women (exposure to radiation is harmful to the fetus), women who are actively breast feeding, patients in renal failure, and those are who not expected to live longer than three months. As MIBG therapy can destroy the thyroid, protective medications (potassium iodide) are started prior to treatment and need to be continued for at least three weeks after therapy concludes. Associated side effects (muscle weakness, nausea, vomiting and hematologic (blood) toxicities, are common, but often minimal, and can be mitigated with slow, steady dosing.
 * Peptide Receptor Radionuclide Therapy (PRRT)
 * The newest of the treatment options, PRRT utilizes the 68-Ga DOTA analogues mentioned above in the functional imaging section. Treatment with 177Lu-DOTATATE first demonstrated success in patients with undifferentiated neuroendocrine tumors and then trials began with metastatic pheochromocytoma patients. In 2019, Vyakaranam et al. published favourable results for their 22 patients who underwent PRRT, with partial response in 2 patients and stable disease (no progression) in the remaining 20 patients. Overall toxicity was low, with no high-grade haematological (blood) or kidney damage reported. 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-related adverse events are minimal, with only 5 out of 102 patients choosing to voluntarily initiate treatment discontinuation. Newer reports have detailed the utility of combining 90Y-DOTATATE with the traditionally studied 177Lu analog and the various possibilities and novel treatment options these combinations will bring to the field. While the overall reported side-effects have been promising, it is important to note that a collaborative effort between the National Institutes of Health and Radboud University Medical Centre reported 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.

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

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 1:2,500 and 1:6,500, meaning that for every 2,500–6,500 people, there is (on average) one person with pheochromocytoma. In the United States, this equates to an annual incidence (new cases per year) of 500 to 1,600 cases. 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 to 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 to 2015, which was a significant increase from their 0.37 cases per 100,000 person-years reported from 1995 to 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:
 * 10% of patients have malignant disease
 * 10% of patients have bilateral (both left and right adrenal glands) disease
 * 10% of patients have extra-adrenal (paraganglioma) disease
 * 10% of patients have inherited (familial disease)

Despite the prominence in many respected textbooks, these guidelines have since been established as inaccurate and are not used in current epidemiological discussions.

As suggested above, incidental imaging has become a major player in the diagnosis of patients with pheochromocytoma, with current estimates that 10–49% of all cases diagnosed after imaging was obtained for another reason. When an adrenal nodule (potential tumor) is discovered on computed tomography or magnetic resonance imaging, there is a 5–10% chance the lesion is a pheochromocytoma. The incidence of adrenal tumors is found in the infographic above, with pheochromocytoma noted in yellow in the top right corner.

History

In 1800, an Irish physician (Charles Sugrue) penned a case report to the London Medical and Physical Journal describing the peculiar case of an 8-year-old male patient who had had seemingly random fits of pain concentrated in the abdomen accompanied by "a hectic flush distinctly marked on each cheek" with a "constant profuse and universal perspiration." Following his death, a group of physicians performed an autopsy to determine cause of death and discovered a six-inch oblong tumor composed of an unknown "yellow-ish coloured substance" coming from the capsula renalis (what is now known as the adrenal gland). 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 to 45%. Retrospective series have postulated that these alarmingly high death rates were due to the lack of a pre-operative blockade with alpha and beta-adrenoceptor antagonist and the need for modern anesthesia practices. From this point forward, physician-scientists have been recognizing patterns in patients with pheochromocytoma and identifying genetic associations and various syndromes.

Society and culture
While a rare disease, there have been several references to pheochromocytoma in popular culture and the media, specifically medical television dramas. Additionally, there is a strong online patient advocacy community that works to connect patients with rare diseases and allows them to meet other individuals who are experiencing similar diagnoses and treatment strategies.

Zebra culture
In the medical community, students are often taught "when you hear hoofbeats, think horses, not zebras." In other words, common diagnoses are common, so healthcare professionals should first rule out what is most expected (the horses) before diving into the rare etiologies that are far less likely to be correct (the zebras). However, the symbol of the zebra has become increasingly powerful to the rare disease community and resulted in several organizations, societies, and special events (Rare Disease Day) to draw attention to the least common option sometimes being the correct diagnosis.

The National Organization for Rare Disorders is a United States–based advocacy parent organization 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 Grey's Anatomy, series regular Henry has a Von Hippel-Lindau (VHL) mutation that has resulted in a pheochromocytoma. The story arc was met with mixed opinions from the rare disease community. The executive director of the VHL Alliance was happy with the portrayal of a VHL patient in mainstream media, but pointed out that of the four scripts she knew of with a VHL patient, three involved a pheochromocytoma, which occurs in less than a fifth of all VHL patients.

A case of pheochromocytoma was featured in the first episode of season 2 of House 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.

title: Pheochromocytoma


text:
Dodo Marmarosa

Michael "Dodo" Marmarosa (December 12, 1925 – September 17, 2002) was an American jazz pianist, composer, and arranger.

Originating in Pittsburgh, Pennsylvania, Marmarosa became a professional musician in his mid-teens, and toured with several major big bands, including those led by Tommy Dorsey, Gene Krupa, and Artie Shaw into the mid-1940s. He moved to Los Angeles in 1945, where he became increasingly interested and involved in the emerging bebop scene. During his time on the West Coast, he recorded in small groups with leading bebop and swing musicians, including Howard McGhee, Charlie Parker, and Lester Young, as well as leading his own bands.

Marmarosa returned to Pittsburgh for health reasons in 1948. He began performing much less frequently, and had a presence only locally for around a decade. Friends and fellow musicians had commented from an early stage that Marmarosa was an unusual character. His mental stability was probably affected by being beaten into a coma when in his teens, by a short-lived marriage followed by permanent separation from his children, and by a traumatic period in the army. He made comeback recordings in the early 1960s, but soon retreated to Pittsburgh, where he played occasionally into the early 1970s. From then until his death three decades later, he lived with family and in veterans' hospitals.

Early life
Marmarosa was born in Pittsburgh, Pennsylvania on December 12, 1925. He had "Italian working-class parents" – Joseph and Carmella. He was the middle of three children, between sisters Audrey and Doris, and grew up in the East Liberty neighborhood of Pittsburgh. Marmarosa attended Peabody High School. He received the uncomplimentary nickname "Dodo" as a child because of his large head, short body, and bird-like nose.

Although he had stated an interest in playing the trumpet, Marmarosa's parents persuaded him to take up the piano, which he began at the age of 9. He received classical music lessons, but was influenced by the jazz playing of Art Tatum, Teddy Wilson, and others after fellow pianist Erroll Garner, four years Marmarosa's elder, introduced him to their music. Marmarosa practiced a lot, until his left and right hands were equally strong.

1941–50
Marmarosa began his professional career around 1941, joining the Johnnie "Scat" Davis orchestra at the age of 15 or 16. He was first mentioned in the national jazz press the following year, appearing in Down Beat magazine for his playing at a jam session. After touring, the Davis orchestra disbanded, so Marmarosa and others then joined Gene Krupa around the end of 1942. After one 1943 Krupa performance in Philadelphia, Marmarosa was beaten into a coma by sailors who accused him of draft dodging. According to clarinetist Buddy DeFranco, who was also attacked by the men, "Dodo was always a little off but he seemed different after that beating. The head injury didn't affect his playing, but I think it created psychological problems for him."

After Krupa's orchestra broke up in the middle of 1943, Marmarosa played in Ted Fio Rito's band for at least a month that summer. He then moved to Charlie Barnet's big band, where he stayed from October 1943 to March 1944. Marmarosa's recording debut was with Barnet in 1943; they recorded "The Moose", a track described by Gunther Schuller as "a veritable masterpiece" on which the 17-year-old pianist played an original blend of nascent bebop and Count Basie-style minimalism. Marmarosa recorded some trio tracks with Krupa and DeFranco in 1944. From April to October of that year he was with Tommy Dorsey, including for the orchestra's appearance in the MGM film Thrill of a Romance. A Dorsey biographer indicated that the pianist was dismissed because the bandleader did not care for the modernistic facets of his playing. Marmarosa soon joined clarinetist Artie Shaw, with whom he stayed until November 1945, as part of a big band and Shaw's small band, the Gramercy Five.

From the early 1940s Marmarosa had searched for and experimented with advanced progressive forms of jazz, and had become increasingly attracted to bebop after meeting and jamming with the leaders of that new movement, Dizzy Gillespie and Charlie Parker. In 1945 Marmarosa moved to Los Angeles. He was pianist in March of the following year for Parker's first recordings for Dial Records. Two of the tracks recorded, "Ornithology" and "Yardbird Suite", have been included in the Grammy Hall of Fame.

Marmarosa recorded extensively as a sideman in the period 1945–47, in both bebop and swing contexts. Leaders of these sessions included Wardell Gray, Lionel Hampton, Mel Tormé, Willie Smith, Lester Young, and, with Marmarosa as house pianist for Atomic Records, Slim Gaillard and Barney Kessel. With a few exceptions, however, Marmarosa only rarely played in public with the leaders whose studio recordings he appeared on during his time on the West Coast. Between the frequent recording sessions, he played "in big bands (especially Boyd Raeburn and Tommy Pederson), at jazz concerts, as a soloist in nightclubs [...] or jamming after hours." Raeburn's orchestra was a progressive group that used "modern arrangements seeking to bridge the gap between bop and advanced European music".

Marmarosa made his first recordings as leader in 1946, with trio tracks that included Ray Brown on bass and Jackie Mills on drums, and in a quartet with saxophonist Lucky Thompson added. He also recorded his only vocal track, "I've Got News for You", in the same year. In 1947 Marmarosa led a trio session for Dial with Harry Babasin on cello and Jackie Mills on drums; these were the first pizzicato jazz cello recordings. In the same year, he featured in some of Gene Norman's Just Jazz concerts, and was given Esquire magazine's New Star (piano) award.

According to Mills, his housemate in 1946–47, "Dodo was the most dedicated of players. He practiced an incredible amount of hours, often all day long. He wouldn't stop to eat. He would eat at the piano with one hand and keep playing with the other. He had no other interests that I was aware of. He could play forever." At this time, Marmarosa did not drink or take hard drugs, but his behavior was often eccentric. Mills reported that "Dodo was just a big kid [...] He never really grew up because he never allowed anything but the piano to be important to him. The piano was his life. He heard things in his head that he wasn't able to play and it frustrated him. Once, he got mad at the old upright piano we had and chopped it up with an axe."

In the spring of 1948 Marmarosa returned to Pittsburgh because of illness. He toured again with "Scat" Davis (April – July 1949) and Shaw (September – November 1949). He left Shaw's band for the final time during one concert after they had twice played Shaw's hit, "Frenesí", Marmarosa had threatened to leave if Shaw called for it again, and the leader had done so after the audience requested a third playing. Shaw reported that Marmarosa "was gentle and fragile, [...and] never learned to deal with the world of a musician." The pianist returned to Pittsburgh in 1950, signed "a term contract" with Savoy Records, and recorded four trio sides for them in July, but the quality did not match his earlier playing.

1951–59
For around a decade, Marmarosa was much less active as a musician. Shaw and DeFranco raised the idea of psychiatric treatment, but the former was rebuffed by Marmarosa himself, and the latter by the pianist's parents: "They were not reconciled to his needing professional help. They were from the old school, they saw it as a stigma. I got into a big argument about it with his father. He really blew up."

In 1952, two years after marrying, Marmarosa moved with his wife and their two daughters to California. The marriage was short lived, and he again returned to his parents' home in Pittsburgh in the fall of that year. His ex-wife remarried and asked him to allow her to change the children's names in exchange for not having to pay her any more money; following the advice of his parents, he signed the documents. A friend of his later stated that never seeing his children again "was the great blight of his life. It tore him apart". Another friend commented more generally that, "After the marriage broke up, he seemed to lose the spark, the drive he once had".

A tour of a few months in Charlie Spivak's band in 1953 preceded Marmarosa being drafted into the army the following year. This exacerbated his problems: several months in a Veteran Administration hospital preceded his discharge, at which point he was in a poor psychological condition. Back in Pittsburgh, where he played locally from March 1956, Marmarosa continued to be erratic, sometimes disappearing for weeks at a time, and giving his money away: "It was like he was on the road to self-destruction", commented trumpeter Danny Conn. Amateur recordings from the pianist's concerts in Pittsburgh in 1958 were released four decades later by Uptown Records.

1960–2002
Marmarosa departed for California by car in 1960, but problems with the vehicle halted him in Chicago. Promoter Joe Segal organized an Argo Records session for him there, but Marmarosa departed suddenly and the recording was delayed until the following year. The resultant trio music from two days in May was released as Dodo's Back! in 1962. Leonard Feather described it as "required listening for anyone with a serious interest in the history of modern jazz piano", but it failed to gain Marmarosa more than a brief resurgence of interest. He made his final studio recordings in 1962. One album from these, Jug & Dodo, contained trio and quartet tracks, with saxophonist Gene Ammons; it was released on Prestige Records more than a decade later. The other, in a quartet with trumpeter Bill Hardman, was released in 1988. Segal commented that Marmarosa "didn't talk much, was very mild-mannered. He just drank an awful lot, shot and a beer all day long. It would've put nine out of ten people under the table, but he was still walking around." The pianist shuttled between Chicago and Pittsburgh for a time, then settled again in the latter.

Marmarosa continued to perform in Pittsburgh, albeit irregularly. Around 1963, DeFranco dropped by; he recalled that the pianist "would play brilliantly for half a tune, then just stop and walk away. He didn't even know who I was". Marmarosa's last performance in public has been dated variously as occurring in 1968 or the early-to-mid 1970s. Diabetes contributed to his permanent retirement. "Even the resurgence of interest in bebop in the 1970s and 80s did not bring him back to national attention", reported The New York Times.

For the rest of his life, Marmarosa alternated between living with his sister Doris' family and in a veterans' hospital, both in the Pittsburgh area. Some of his friends blamed Marmarosa's family for keeping him in their home because of shame about his mental problems, and suggested that the family blamed musicians and music for his instability. Marmarosa himself did not explain his withdrawal from performing. Irritated by telephone calls from a fan seeking an interview in 1992, Marmarosa passed on the news that he had died; this led to premature obituaries being published in two British newspapers. He sometimes played piano in the family's basement or for other residents at the hospital. His mother died in 1995, after his father. Marmarosa died of a heart attack on September 17, 2002, in a veterans' hospital in Pittsburgh. He was survived by his two sisters.

Playing style and influence
Pianist Dick Katz wrote that, "In the opinion of many, Dodo Marmarosa was the most gifted of all the pianists who figured in the bebop saga. Blessed with a beautiful legato touch and a fluid technique, he developed an original style, which [...] blended perfectly with the bop idiom, as well as with earlier styles. He combined advanced chordal and scalar elements with graceful rhythmic phrasing."

In some of his 1944 playing, Marmarosa was progressively bebop-directed, employing melodies derived from the harmony and varying the rhythmic positioning of accents; soon after, he added more space to his playing, using shorter sequences of notes than typical in bebop. Jazz critic Marc Myers, in comparing Marmarosa with other pianists of the early bebop period, observed that he was less aggressive than Bud Powell, and more expressive and complex than Al Haig, and that he "had a punctuating, full-keyboard approach, developing ideas in the middle and widening out to express them."

Critic and musician Brian Priestley wrote that "What was so distinctive about Dodo's work was partly his harmonic sense and knowledge of the additional notes [...in bebop.] Many pianists were trying to find ways to voice these satisfactorily in full chording, but none did so as pleasingly or as fluently as Marmarosa. Partly it was also the way he alternated between employing his hands together and in opposition to each other, and allied to this was his unusual time feeling."

By the time of his 1960s recordings, Marmarosa had a more relaxed playing style. Biographers commented that "his even, classically derived articulation had given way to a more rhythmically pronounced, jazz-oriented playing, and, above all, his musical personality seemed still more determined and coherent."

Pianist Cecil Taylor commented in 1961 that "The first modern pianist who made any impression on me was Dodo Marmarosa, with Charlie Barnet." Marmarosa also encouraged DeFranco to take up bebop.

Discography
Compilations of previously released material, and recordings from or for radio broadcasts, are not listed.

Singles as sideman
Tracks recorded but not released as singles are not listed.

Main sources:

Filmography

 * Thrill of a Romance (made 1944; released 1945)

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Dodo Marmarosa


text:
Ventricle

Ventricle may refer to:

 * Ventricle (heart), the pumping chambers of the heart
 * Ventricular system in the brain
 * Ventricle of the larynx, a structure in the larynx

title: Ventricle


text:
Devil's advocate

The advocatus diaboli (Latin for Devil's advocate) is a former official position within the Catholic Church, the Promoter of the Faith: one who "argued against the canonization (sainthood) of a candidate in to uncover any character flaws or misrepresentation of the evidence favoring canonization".

In common language, the phrase "playing devil's advocate" describes a situation where someone, given a certain point of view, takes a position they do not necessarily agree with (or simply an alternative position from the accepted norm), for the sake of debate or to explore the thought further using valid reasoning that both disagrees with the subject at hand and proves their own point valid. Despite being medieval in origin, this idiomatic expression is one of the most popular present-day English idioms used to express the concept of arguing against something without actually being committed to the contrary view. Playing devil's advocate is considered a form of the Socratic method.

Origin and history
During the canonization process employed by the Catholic Church, the 'Promoter of the Faith' (promotor fidei), popularly known as the Devil's advocate (advocatus diaboli), was a canon lawyer appointed by Church authorities to argue against the canonization of a candidate. It was this person's job to take a skeptical view of the candidate's character, to look for holes in the evidence, to argue that any miracles attributed to the candidate were fraudulent, and so on. The Devil's advocate opposed 'God's advocate' (advocatus Dei; also known as the 'Promoter of the Cause'), whose task was to make the argument in favor of canonization. During the investigation of a cause, this task is now performed by the 'Promoter of Justice' (promotor iustitiae), who is in charge of examining the accuracy of the inquiry on the saintliness of the candidate. The Promoter of the Faith remains a figure in the Congregation of the Causes of Saints and is also known as the Prelate Theologian.

The office was established in 1587 during the reign of Pope Sixtus V. The first formal mention of such an officer is found in the canonization of St Lawrence Justinian under Pope Leo X (1513–1521). Pope John Paul II reduced the power and changed the role of the office in 1983. In cases of controversy, the Vatican may still seek to solicit the testimony of critics of a candidate for canonization. One notable example of this was in 2003, when author Christopher Hitchens, an atheist and outspoken critic of Mother Teresa, was interviewed as part of her beatification hearings.

Effectiveness
Psychologist Charlan Jeanne Nemeth writes that inauthentic dissent (assigning someone to act as a Devil's advocate) is considerably less effective in improving group decision-making than authentic dissent. She also writes that inauthentic dissent can cause people to become more entrenched in their original beliefs, the opposite of the intended purpose e.g. in businesses that use this technique.

title: Devil's advocate


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Multiple endocrine neoplasia

Multiple endocrine neoplasia (abbreviated MEN) is a condition which encompasses several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. Benign or malignant tumors of nonendocrine tissues occur as components of some of these tumor syndromes.

MEN syndromes are inherited as autosomal dominant disorders.

Related conditions
Although not officially categorized as multiple endocrine neoplasia syndromes, Von Hippel–Lindau disease and Carney complex are two other autosomal dominant endocrine tumor syndromes with features that overlap the clinical features of the MEN syndromes. Although not transmitted in the germline, McCune–Albright syndrome is a genetic disorder characterized by endocrine neoplastic features involving endocrine glands that overlap with those involved in MEN1 or MEN2.

Comparison
Percentages in the table below refer to the percentage of people with the MEN type who develop the neoplasia type. * - of patients with MEN1 and gastrinoma

FMTC = familial medullary thyroid cancer

MEN 2B is sometimes known as MEN 3 and the designation varies by institution (c.f. www.ClinicalReview.com). Although a variety of additional eponyms have been proposed for MEN2B (e.g. Williams-Pollock syndrome, Gorlin-Vickers syndrome, and Wagenmann–Froboese syndrome), none ever gained sufficient traction to merit continued use and, indeed, are all but abandoned in the medical literature. Another early report was Schimke et al. in 1968.

OMIM also includes a fourth form of multiple endocrine neoplasia ("MEN4"), associated with CDKN1B. The presentation is believed to overlap that of MEN1 and MEN2.

The MEN1 gene
The MEN1 gene consists of ten exons, spanning about 10 kb, and encodes a 610 amino acid protein named menin. The first exon and the last part of exon 10 are not translated. The main transcript of 2.8 kb has been described in a large variety of human tissues (pancreas, thymus, adrenal glands, thyroid, testis, leukocytes, heart, brain, lung, muscle, small intestine, liver, and kidney); an additional transcript of approximately 4 kb has been detected in pancreas and thymus, suggesting tissue-specific alternative splicing.

The Menin Protein
Menin is a 610 amino acid (67Kda) nuclear protein, highly conserved from mouse (98%), rat (97%) and, more distantly, zebrafish (75%) and Drosophila (47%) (47-51). Human and mouse MEN1 amino acid sequences share 95.8% identity and 98.4% similarity. Analysis of menin amino acid sequence did not reveal homologies to any other known human or mammalian protein, sequence motif, or signal peptide. The absence of significant homology to any other protein complicates efforts to elucidate the functions of menin.

Pathophysiology
MEN1 follows Knudson’s “two-hit” model for tumor suppressor gene carcinogenesis (30). The first hit is a heterozygous MEN1 germline mutation, inherited from one parent (familial cases) or developed in an early embryonic stage (sporadic cases) and present in all cells at birth. The second hit is a MEN1 somatic mutation, usually a large deletion, that occurs in the predisposed endocrine cell as loss of the remaining wild-type allele and gives cells the survival advantage needed for tumor development.

Mnemonic
A useful mnemonic to remember the associated neoplasias is below:

MEN I (3 Ps) - Pituitary, Parathyroid, Pancreatic MEN IIa (2Ps, 1M) - Pheochromocytoma, Parathyroid, Medullary Thyroid Ca MEN IIb (1P, 2Ms) - Pheochromocytoma, Medullary Thyroid Ca, Marfanoid habitus/mucosal neuroma

MEN1 mutations in multiple endocrine neoplasia patients and clinical genetics
MEN1 gene mutations can be identified in 70–95% of MEN1 patients and in about 20% of familial isolated hyperparathyroidism cases. Almost all patients are heterozygous for mutations. One affected family has been identified with individuals both homozygous and heterozygous for MEN1 mutations. In this family, there was no difference in disease history between the homozygous and heterozygous mutation carriers.

50% of patients develop signs and symptoms by 20 years of age and more than 95% have symptoms by 40 years of age. There is significant intra- and inter-familial variability in the age of onset, the severity of disease, and tumor types. Despite numerous studies, no genotype-phenotype correlations have been established, suggesting that unknown genetic and environmental modifiers are involved in the expression of the MEN1 phenotype.

Manifestations
Multiple Endocrine Neoplasia type 1 (MEN1) is a rare hereditary endocrine cancer syndrome characterized primarily by tumors of the parathyroid glands (95% of cases), endocrine gastroenteropancreatic (GEP) tract (30–80% of cases), and anterior pituitary (15–90% of cases). Other endocrine and non-endocrine neoplasms including adrenocortical and thyroid tumors, visceral and cutaneous lipomas, meningiomas, facial angiofibromas and collagenomas, and thymic, gastric, and bronchial carcinoids also occur. The phenotype of MEN1 is broad, and over 20 different combinations of endocrine and non-endocrine manifestations have been described. MEN1 should be suspected in patients with an endocrinopathy of two of the three characteristic affected organs, or with an endocrinopathy of one of these organs plus a first-degree relative affected by MEN1 syndrome.

MEN1 patients usually have a family history of MEN1. Inheritance is autosomal dominant; any affected parent has a 50% chance to transmit the disease to his or her progeny. MEN1 gene mutations can be identified in 70–95% of MEN1 patients.

Many endocrine tumors in MEN1 are benign and cause symptoms by overproduction of hormones or local mass effects, while other MEN1 tumors are associated with an elevated risk for malignancy. About one-third of patients affected with MEN1 will die early from MEN1-related cancer or associated malignancy. Entero-pancreatic gastrinomas and thymic and bronchial carcinoids are the leading cause of morbidity and mortality. Consequently, the average age of death in untreated individuals with MEN1 is significantly lower (55.4 years for men and 46.8 years for women) than that of the general population.

Recommended cancer surveillance
A recommend surveillance program for Multiple Endocrine Neoplasia Type 1 has been suggested by the International Guidelines for Diagnosis and Therapy of MEN syndromes group.

History
In 1903 Erdheim described the case of an acromegalic patient with a pituitary adenoma and three enlarged parathyroid glands.

In 1953 Underdahl et al. reported a case series of 8 patients with a syndrome of pituitary, parathyroid, and pancreatic islet adenomas.

In 1954 Wermer noted that this syndrome was transmitted as a dominant trait.

In 1959 Hazard et al. described medullary (solid) thyroid carcinoma.

In 1961 Sipple described a combination of a pheochromocytoma, medullary thyroid carcinoma and parathyroid adenoma.

In 1966 Williams et al. described the combination of mucosal neuromas, pheochromocytoma and medullary thyroid carcinoma.

In 1968 Steiner et al. introduced the term "multiple endocrine neoplasias" (MEN) to describe disorders featuring combinations of endocrine tumors and proposed the terms 'Wermer syndrome' for MEN 1 and 'Sipple syndrome' for MEN 2.

In 1974 Sizemore et al. showed that the MEN 2 category included two groups of patients with MTC and pheochromocytoma: one with parathyroid disease and a normal appearance (MEN 2A) and the other without parathyroid disease but with mucosal neuromas and mesodermal abnormalities (MEN 2B).

In 1988 the MEN1 locus was assigned to Chromosome 11 (11q13).

In 1993 mutations in the RET oncogene were shown to be the cause of MEN 2A by Lois Mulligan, working in the laboratory of Bruce Ponder in Cambridge.

In 1998 the MEN1 gene was cloned.

Terminology
The older names, "multiple endocrine adenomas" and "multiple endocrine adenomatosis" (MEA), have been replaced by the current terminology.

The term multiple endocrine neoplasias are used when two or more endocrine tumor types, known to occur as a part of one of the defined MEN syndromes, occurs in a single patient and there is evidence for either a causative mutation or hereditary transmission. The presence of two or more tumor types in a single patient does not automatically designate that individual as having MEN because there is a small statistical chance that the development of two "sporadic" tumors that occur in one of the MEN syndromes could occur by chance.

The term "multiple endocrine neoplasia" was introduced in 1968, but descriptions of the condition date back to 1903.

title: Multiple endocrine neoplasia


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Syndrome

A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. The word derives from the Greek σύνδρομον, meaning "concurrence". When a syndrome is paired with a definite cause this becomes a disease. In some instances, a syndrome is so closely linked with a pathogenesis or cause that the words syndrome, disease, and disorder end up being used interchangeably for them. This substitution of terminology often confuses the reality and meaning of medical diagnoses. This is especially true of inherited syndromes. About one third of all phenotypes that are listed in OMIM are described as dysmorphic, which usually refers to the facial gestalt. For example, Down syndrome, Wolf–Hirschhorn syndrome, and Andersen–Tawil syndrome are disorders with known pathogeneses, so each is more than just a set of signs and symptoms, despite the syndrome nomenclature. In other instances, a syndrome is not specific to only one disease. For example, toxic shock syndrome can be caused by various toxins; another medical syndrome named as premotor syndrome can be caused by various brain lesions; and premenstrual syndrome is not a disease but simply a set of symptoms.

If an underlying genetic cause is suspected but not known, a condition may be referred to as a genetic association (often just "association" in context). By definition, an association indicates that the collection of signs and symptoms occurs in combination more frequently than would be likely by chance alone.

Syndromes are often named after the physician or group of physicians that discovered them or initially described the full clinical picture. Such eponymous syndrome names are examples of medical eponyms. Recently, there has been a shift towards naming conditions descriptively (by symptoms or underlying cause) rather than eponymously, but the eponymous syndrome names often persist in common usage.

The defining of syndromes has sometimes been termed syndromology, but it is usually not a separate discipline from nosology and differential diagnosis generally, which inherently involve pattern recognition (both sentient and automated) and differentiation among overlapping sets of signs and symptoms. Teratology (dysmorphology) by its nature involves the defining of congenital syndromes that may include birth defects (pathoanatomy), dysmetabolism (pathophysiology), and neurodevelopmental disorders.

Subsyndromal
When there are a number of symptoms suggesting a particular disease or condition but does not meet the defined criteria used to make a diagnosis of that disease or condition. This can be a bit subjective because it is ultimately up to the clinician to make the diagnosis. This could be because it has not advanced to the level or passed a threshold or just similar symptoms cause by other issues. Subclinical is synonymous since one of its definitions is "where some criteria are met but not enough to achieve clinical status"; but subclinical is not always interchangeable since it can also mean "not detectable or producing effects that are not detectable by the usual clinical tests"; i.e., asymptomatic.

General medicine
In medicine, a broad definition of syndrome is used, which describes a collection of symptoms and findings without necessarily tying them to a single identifiable pathogenesis. Examples of infectious syndromes include encephalitis and hepatitis, which can both have several different infectious causes. The more specific definition employed in medical genetics describes a subset of all medical syndromes.

Psychiatry and psychopathology
Psychiatric syndromes often called psychopathological syndromes (psychopathology refers both to psychic dysfunctions occurring in mental disorders, and the study of the origin, diagnosis, development, and treatment of mental disorders).

In Russia those psychopathological syndromes are used in modern clinical practice and described in psychiatric literature in the details: asthenic syndrome, obsessive syndrome, emotional syndromes (for example, manic syndrome, depressive syndrome), Cotard's syndrome, catatonic syndrome, hebephrenic syndrome, delusional and hallucinatory syndromes (for example, paranoid syndrome, paranoid-hallucinatory syndrome, Kandinsky-Clérambault's syndrome also known as syndrome of psychic automatism, hallucinosis), paraphrenic syndrome, psychopathic syndromes (includes all personality disorders), clouding of consciousness syndromes (for example, twilight clouding of consciousness, amential syndrome also known as amentia, delirious syndrome, stunned consciousness syndrome, oneiroid syndrome), hysteric syndrome, neurotic syndrome, Korsakoff's syndrome, hypochondriacal syndrome, paranoiac syndrome, senestopathic syndrome, encephalopathic syndrome.

Some examples of psychopathological syndromes used in modern Germany are psychoorganic syndrome, depressive syndrome, paranoid-hallucinatory syndrome, obsessive-compulsive syndrome, autonomic syndrome, hostility syndrome, manic syndrome, apathy syndrome.

Münchausen syndrome, Ganser syndrome, neuroleptic-induced deficit syndrome, olfactory reference syndrome are also well-known.

History
The most important psychopathological syndromes were classified into three groups ranked in order of severity by German psychiatrist Emil Kraepelin (1856—1926). The first group, which includes the mild disorders, consists of five syndromes: emotional, paranoid, hysterical, delirious, and impulsive. The second, intermediate, group includes two syndromes: schizophrenic syndrome and speech-hallucinatory syndrome. The third includes the most severe disorders, and consists of three syndromes: epileptic, oligophrenic and dementia. In Kraepelin's era, epilepsy was viewed as a mental illness; Karl Jaspers also considered "genuine epilepsy" a "psychosis", and described "the three major psychoses" as schizophrenia, epilepsy, and manic-depressive illness.

Medical genetics
In the field of medical genetics, the term "syndrome" is traditionally only used when the underlying genetic cause is known. Thus, trisomy 21 is commonly known as Down syndrome.

Until 2005, CHARGE syndrome was most frequently referred to as "CHARGE association". When the major causative gene (CHD7) for the condition was discovered, the name was changed. The consensus underlying cause of VACTERL association has not been determined, and thus it is not commonly referred to as a "syndrome".

Other fields
In biology, "syndrome" is used in a more general sense to describe characteristic sets of features in various contexts. Examples include behavioral syndromes, as well as pollination syndromes and seed dispersal syndromes.

In orbital mechanics and astronomy, Kessler syndrome refers to the effect where the density of objects in low Earth orbit (LEO) is high enough that collisions between objects could cause a cascade in which each collision generates space debris that increases the likelihood of further collisions.

In quantum error correction theory syndromes correspond to errors in code words which are determined with syndrome measurements, which only collapse the state on an error state, so that the error can be corrected without affecting the quantum information stored in the code words.

Naming
There is no set common convention for the naming of newly identified syndromes. In the past, syndromes were often named after the physician or scientist who identified and described the condition in an initial publication. These are referred to as "eponymous syndromes". In some cases, diseases are named after the patient who initially presents with symptoms, or their home town (Stockholm syndrome). There have been isolated cases of patients being eager to have their syndromes named after them, while their physicians are hesitant. When a syndrome is named after a person, there is some difference of opinion as to whether it should take the possessive form or not (e.g. Down syndrome vs. Down's syndrome). North American usage has tended to favor the non-possessive form, while European references often use the possessive. A 2009 study demonstrated a trend away from the possessive form in Europe in medical literature from 1970 through 2008.

History
Avicenna, in The Canon of Medicine (published 1025) helped lay the groundwork for the idea of a syndrome and pioneered in the diagnosis of a specific disease. The concept of a medical syndrome was further developed in the 17th century by Thomas Sydenham.

Underlying cause
Even in syndromes with no known etiology, the presence of the associated symptoms with a statistically improbable correlation normally leads the researchers to hypothesize that there exists an unknown underlying cause for all the described symptoms.

title: Syndrome


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FIM

FIM may refer to:

Organizations and companies

 * Fédération Internationale de Motocyclisme, the International Motorcycling Federation
 * Flint Institute of Music, in Michigan, United States
 * Fox Interactive Media, now News Corp. Digital Media
 * Institute for Mathematical Research (German: Forschungsinstitut für Mathematik), at ETH Zurich
 * Independent Moralizing Front (Spanish: Frente Independiente Moralizador), a defunct Peruvian political party
 * International Federation of Musicians (Federation Internationale des Musiciens), a global union federation

Science and technology

 * Facing Identification Mark, a bar code designed by the United States Postal Service
 * Field ion microscope, used to image the arrangement of atoms
 * File integrity monitoring, used to validate software files
 * Fim switch, in E. coli
 * Flood Inundation Map
 * Flow-following, finite-volume Icosahedral Model, a numerical weather prediction model
 * Focused impedance measurement
 * Forefront Identity Manager, identity management software

Other

 * Finnish markka, the former currency of Finland
 * First-in-man study, in medical clinical trials
 * Fisher information matrix, in mathematical statistics
 * Flight interruption manifest, a substitute airline ticket
 * Functional Independence Measure, tool for assessing functional capacities of patients undergoing rehabilitation
 * Friendship Is Magic aka My Little Pony: Friendship Is Magic, a 2010 animated series

title: FIM