Pheochromocytoma

Sporadic vs. Hereditary Cases

• Adrenal vs. Extra-Adrenal Origins: Approximately 85% of pheochromocytomas originate in the adrenal medulla from catecholamine-producing chromaffin cells. The remaining 15% arise from extra-adrenal chromaffin cells, forming paragangliomas.
• Sporadic Cases: Most pheochromocytomas occur sporadically, though up to 40% are hereditary in adults, with an even higher hereditary proportion in pediatric cases (up to 80%).
• Hereditary Cases: Familial syndromes associated with pheochromocytomas include:
  • Multiple Endocrine Neoplasia type 2 (MEN2) – caused by mutations in the RET proto-oncogene.
  • Von Hippel-Lindau (VHL) syndrome – linked to mutations in the VHL gene.
  • Neurofibromatosis type 1 (NF1) – associated with mutations in the NF1 gene.
    
    

Genetic Basis and Molecular Clustering

• Identified Genes: More than 20 genes have been implicated in pheochromocytoma development, with half of all germline mutations affecting succinate dehydrogenase (SDH) subunits.
• Key Mutations:
  • Succinate Dehydrogenase (SDH) Complex: SDHA, SDHB, SDHC, SDHD, and SDHAF2.
  • Other Mutated Genes: Fumarate hydratase (FH), malate dehydrogenase 2 (MDH2), transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), and hypoxia-inducible factor 2-alpha (HIF2A/EPAS1).
  • Somatic Driver Mutations: Found in RET, VHL, NF1, EPAS1, and additional oncogenic regulators like HRAS, CSDE1, ATRX, TERT, and MAML3.
• Molecular Clustering of Pheochromocytomas and Paragangliomas (PPGLs):
  • Pseudohypoxic PPGLs: Mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2, and HIF2A/EPAS1.
  • Kinase Signaling PPGLs: Involves RET, NF1, TMEM127, MAX, and HRAS.
  • Wnt Signaling PPGLs: Driven by CSDE1 and MAML3 mutations.
    
    

MEN2-Associated Pheochromocytomas

• MEN 2A (Sipple Syndrome):
  • Caused by RET proto-oncogene mutations, primarily affecting codons 609, 611, 618, 620 (exon 10) and 634 (exon 11).
  • Associated with:
    • Medullary thyroid carcinoma (~95% risk).
    • Parathyroid adenomas (~20-30% risk).
    • Pheochromocytomas (~50% risk).
    • Hirschsprung disease.
• MEN 2B:
  • Characterised by:
    • Medullary thyroid carcinoma.
    • Pheochromocytomas (~50% risk).
    • Mucosal neuromas and marfanoid habitus.
    • Intestinal ganglioneuromatosis.
  • Nearly all cases are associated with RET exon 16 (codon 918) mutations.
    
    

Other Genetic Aetiologies

• MAX Mutations:
  • Loss-of-function in MYC-associated factor X (MAX) correlates with metastatic potential.
  • Germline mutations in MAX contribute to ~1% of pheochromocytomas.
• GDNF Gene:
  • Involved in adrenal and extra-adrenal pheochromocytoma development.
  • Associated with central hypoventilation syndrome and Hirschsprung disease.
• TMEM127 Mutations:
  • Leads to pheochromocytoma development between young adulthood and middle age.
  • Inherited in an autosomal dominant fashion with incomplete penetrance.
    
    

Von Hippel-Lindau (VHL) Disease

• Associated with pheochromocytomas, cerebellar hemangioblastomas, renal cell carcinoma, pancreatic cysts, and epididymal cystadenomas.
• VHL gene mutations affect oxygen-sensing pathways, cellular senescence, and cilia formation.
  
  

Neurofibromatosis and Other Neuroectodermal Disorders

• Neurofibromatosis type 1 (NF1):
  • Characterised by café-au-lait spots, neurofibromas, and optic gliomas.
  • 1-5% of patients with pheochromocytomas have NF1.
• Other Disorders:
  • Tuberous sclerosis (Bourneville disease, epiloia).
  • Sturge-Weber syndrome.
    
    

Biochemical Variability in Pheochromocytomas

• Some pheochromocytomas produce excess calcitonin, opioid peptides, somatostatin, corticotropin (ACTH), or vasoactive intestinal peptide (VIP).
• ACTH hypersecretion may cause Cushing syndrome, while VIP excess leads to watery diarrhoea.
  
  

Succinate Dehydrogenase (SDH) Mutations and Tumor Risk

• SDHD Mutations:
  • Cause paragangliomas, pheochromocytomas, and other tumors.
  • Typically exhibit paternal imprinting.
• SDHB Mutations:
  • Increase risk of carotid body tumors, paragangliomas, and metastatic transformation.
  • Inherited in an autosomal dominant manner.
• SDHC and SDHAF2 Mutations:
  • Associated with paragangliomas, with some reports of maternal inheritance.
• Additional SDH Mutations:
  • Include SDHA, SDHAF2, and recently identified SDH-complex assembly factor 2 (SDHAF2).
    
    

Epigenetic and Structural Syndromes

• Hemihyperplasia (Hemihypertrophy):
  • Increases tumor risk and can occur isolated or as part of larger syndromes:
    • Beckwith-Wiedemann syndrome.
    • Proteus syndrome.
  • Associated with paternal uniparental disomy at 11p15.
  • Epigenetic regulation of LIT1 and H19 genes is critical in disease development.

Catecholamine Overproduction and Secretion Patterns

• Pheochromocytomas originate from chromaffin cells in the adrenal medulla, while paragangliomas arise from neural crest-derived sympathetic paraganglia.
• These tumors secrete catecholamines, primarily norepinephrine and epinephrine, with some tumors also producing dopamine.
• Secretion Patterns:
  • Paroxysmal secretion: Leads to episodic hypertension and tachyarrhythmias.
  • Continuous secretion: Causes sustained hypertension.
  • Mixed secretion: Displays intermittent spikes in blood pressure.
    
    

Biochemical Pathways of Catecholamine Synthesis

• Catecholamines are synthesised through a sequential biochemical pathway:
  1. Tyrosine hydroxylase catalyses the conversion of tyrosine to dihydroxyphenylalanine (DOPA).
  2. DOPA decarboxylase converts DOPA into dopamine.
  3. Dopamine β-hydroxylase converts dopamine to norepinephrine.
  4. Phenylethanolamine-N-methyltransferase (PNMT) methylates norepinephrine to epinephrine.
• In pheochromocytomas, catecholamines are stored in vesicles and released into circulation, where they exert cardiovascular effects.
  
  

Adrenergic Receptor Activation and Cardiovascular Effects

• Alpha-Adrenergic Receptors:
  • α-1 stimulation: Vasoconstriction, elevated blood pressure, increased cardiac contractility, glycogenolysis, and intestinal relaxation.
  • α-2 stimulation: Inhibits norepinephrine release at synaptic terminals.
• Beta-Adrenergic Receptors:
  • β-1 stimulation: Increased heart rate and contractility.
  • β-2 stimulation: Peripheral vasodilation and bronchodilation.
• Receptor Selectivity:
  • Epinephrine binds equally to β-1 and β-2 receptors.
  • Norepinephrine has 10-fold greater affinity for β-1 than β-2 and preferentially binds α-1 receptors, contributing to sustained hypertension.
  • Dopamine acts on α-2 receptors, modulating vascular tone.
    
    

Differences in Catecholamine Secretion Based on Tumor Type

• Adrenergic Phenotype (Pheochromocytoma):
  • Increased adrenaline/metanephrine or both adrenaline/metanephrine and noradrenaline/normetanephrine.
• Noradrenergic Phenotype (Paraganglioma):
  • Elevated noradrenaline/normetanephrine with little or no adrenaline/metanephrine due to a lack of PNMT required for epinephrine synthesis.
• Hereditary Syndromes and Secretory Profiles:
  • VHL-associated tumors predominantly produce norepinephrine.
  • MEN 2 and NF1-associated tumors secrete both epinephrine and norepinephrine.
  • SDHB/SDHD mutation-related tumors frequently produce dopamine, which has been linked to a higher malignant potential.
    
    

Triggers for Catecholamine Release

• Pheochromocytomas lack direct neural innervation; catecholamine release is not triggered by normal physiological stimuli.
• Factors that can precipitate hypertensive crises include:
  • Anesthesia induction
  • Opiates
  • Dopamine antagonists (e.g., metoclopramide)
  • Beta-blockers (without prior alpha-blockade)
  • Cold medications
  • Tricyclic antidepressants and cocaine
  • Childbirth

Pathophysiological Consequences of Catecholamine Excess

• Cardiac Effects:
  • Persistent adrenergic stimulation causes hypertension, tachyarrhythmias, and cardiac hypertrophy.
  • Chronic catecholamine excess can result in cardiomyopathy, resembling Takotsubo (stress-induced) cardiomyopathy.
  • Some patients develop pulmonary oedema upon initiating beta-blockade due to unopposed alpha-receptor activation.
• Metabolic Effects:
  • Elevated catecholamines promote glycogenolysis and gluconeogenesis, leading to hyperglycemia and insulin resistance.
  • Increased lipolysis contributes to weight loss.
• Neurological Effects:
  • Sudden catecholamine surges can cause headaches, anxiety, tremors, and hyperhidrosis.
  • Panic-attack-like symptoms are commonly reported, particularly in epinephrine-producing tumors.
• Renal Effects:
  • Sustained hypertension can lead to renal dysfunction, proteinuria, and secondary erythrocytosis.
• Gastrointestinal Effects:
  • Intestinal relaxation from alpha-adrenergic stimulation can result in constipation.
  • Tumors secreting vasoactive intestinal peptide (VIP) can cause watery diarrhoea.
    
    

Tumor Size and Secretory Activity

• A retrospective study found a direct correlation between tumor size and catecholamine levels:
  • Tumors ≥2.3 cm in diameter produce catecholamine/metanephrine levels three times the upper limit of normal.
  • Larger tumors are associated with greater hemodynamic instability and higher risk of hypertensive crises.
• Despite surgical removal, persistent cardiac fibrosis and strain have been observed on cardiac MRI, suggesting long-term catecholamine toxicity.
  
  

Malignant Potential and Metastatic Risk

• Although histological criteria do not reliably predict malignancy, about 10-15% of pheochromocytomas and paragangliomas metastasise.
• Factors Increasing Malignancy Risk:
  • Tumor size >5 cm (pheochromocytomas) or >4 cm (paragangliomas).
  • Gross large vessel invasion.
  • Extra-adrenal location.
  • Germline SDHB mutations, which have been linked to higher metastatic potential.
• Metastatic Sites:
  • Bone, brain, and lymph nodes (as these sites lack normal paraganglionic tissue).
  • Metastases can occur decades after tumor resection, necessitating long-term follow-up.
    
    

Incidence and Prevalence

• Pheochromocytomas are rare tumors, with an estimated annual incidence of 0.8 per 100,000 person-years.
• Reported prevalence varies depending on the population studied:
  • 0.05%–0.2% of hypertensive individuals are found to have pheochromocytomas.
  • In autopsy series, up to 0.1% of patients have undiagnosed pheochromocytomas, suggesting a significant proportion remain asymptomatic.
  • In a large US study, the estimated prevalence of pheochromocytoma and paraganglioma (PPGL) was between 1:2,500 and 1:6,500.
  • An Olmsted County study reported a prevalence of 8 per 100,000 as of 2017.
    
    

Geographic and Temporal Trends

• A Dutch study observed an increase in the age-standardized incidence rate (ASR) of pheochromocytomas and sympathetic paragangliomas from 0.29 per 100,000 person-years (1995–1999) to 0.46 per 100,000 (2011–2015).
• The ASR for sympathetic paragangliomas also rose during the same period.
• Researchers attributed these increases to greater use of imaging and biochemical testing, leading to improved detection.
  
  

Presentation and Diagnostic Trends

• Approximately 10% of pheochromocytomas are discovered incidentally, often as adrenal masses on imaging.
• Up to 14% of adrenal incidentalomas are later confirmed to be pheochromocytomas.
• Sporadic pheochromocytomas are typically diagnosed based on symptoms or incidentally on imaging.
• Hereditary pheochromocytomas are often detected earlier due to genetic testing or biochemical screening in at-risk individuals.
  
  

Demographic Factors

• Age at Diagnosis:
  • Most commonly diagnosed between the third and fifth decades of life, with an average age of 43 years.
  • Approximately 10% of cases occur in children, with 50% of pediatric cases being solitary intra-adrenal tumors, while 25% are bilateral and 25% are extra-adrenal.
  • A study found that patients with sporadic pheochromocytoma were diagnosed at an older age (54.5 years) compared to those with hereditary pheochromocytomas (40.8 years).
• Sex and Ethnicity:
  • Occurs equally in men and women.
  • Reported across all racial groups, though lower diagnosis rates have been observed in Black populations.
    
    

Familial vs. Sporadic Cases

• Sporadic cases account for the majority of pheochromocytomas.
• Up to 40% of cases are associated with hereditary syndromes, including:
  • Von Hippel-Lindau (VHL) syndrome: 10%–20% of patients develop pheochromocytomas.
  • Multiple endocrine neoplasia type 2 (MEN2): Up to 50% of patients develop pheochromocytomas.
  • Neurofibromatosis type 1 (NF1): Occurs in 2%–3% of affected individuals.
• Hereditary tumors tend to be:
  • Bilateral when adrenal.
  • More likely to present as paragangliomas.
  • Diagnosed at a younger age compared to sporadic cases.
    
    

Underdiagnosis and Missed Cases

• Many pheochromocytomas remain undiagnosed, often detected post-mortem.
• In one Mayo Clinic retrospective review, 50% of cases were first identified at autopsy.
• A single-center study of 4,180 hypertensive patients in Brooklyn identified pheochromocytomas in 0.2% of cases, highlighting the rarity and diagnostic challenges.
  
  

Key Symptoms and Paroxysmal Spells

• The classic triad of pheochromocytoma symptoms includes:
  • Headache (occurring in up to 90% of symptomatic cases).
  • Palpitations (often episodic, occurring in 60% of cases).
  • Diaphoresis (60%–70% of cases).
• These symptoms frequently present as paroxysmal spells and are strongly suggestive of pheochromocytoma when associated with:
  • Severe hypertension (sustained or paroxysmal, found in 95% of cases).
  • Tachycardia or tachyarrhythmias.
• Paroxysmal spells vary in duration (seconds to hours) and frequency (monthly to several times daily), worsening as the tumor grows.
• Precipitants of hypertensive crises include:
  • Exercise, stress, anxiety.
  • Tyramine-rich foods (e.g., aged cheese, red wine).
  • Certain medications (e.g., beta-blockers, tricyclic antidepressants, dopamine antagonists, monoamine oxidase inhibitors, metoclopramide, corticosteroids).
  • Surgical procedures or anesthesia induction.
    
    

Additional Symptoms

• Adrenergic overactivity-related symptoms:
  • Tremor
  • Pallor (due to intense vasoconstriction).
  • Anxiety, sense of doom (commonly seen in adrenaline-secreting tumors).
  • Flank pain or epigastric pain.
  • Weakness, nausea.
  • Weight loss (due to increased metabolic rate).
  • Constipation (resulting from intestinal relaxation via alpha-adrenergic stimulation).
    
    

Risk Factors and Family History

• Hereditary syndromes associated with pheochromocytoma:
  • Multiple Endocrine Neoplasia type 2 (MEN2) (pheochromocytomas occur in 50% of MEN2A and MEN2B cases).
  • Von Hippel-Lindau (VHL) disease (lifetime pheochromocytoma risk 10%–20%).
  • Neurofibromatosis type 1 (NF1) (pheochromocytoma risk 2%–3%).
  • Succinate dehydrogenase (SDH) gene mutations (SDHB, SDHC, SDHD) (linked to paragangliomas, with a higher malignancy risk for SDHB mutations).
• Family history of:
  • Pheochromocytomas, paragangliomas.
  • Medullary thyroid carcinoma.
  • Hypertensive crises.
  • Hypercalcemia or endocrine tumors.
    
    

History of Prior Pheochromocytoma

• Patients with a history of pheochromocytoma require long-term surveillance, as the risk of recurrence is high, especially in familial cases.
  
  

Hypertension Patterns

• Paroxysmal Hypertension:
  • 45% of cases have episodic blood pressure elevations.
  • May be triggered by stress, medications, or anaesthesia.
• Sustained Hypertension:
  • Found in 50% of cases.
  • Can be mistaken for essential hypertension.
• Normotensive Cases:
  • Up to 15% of patients have normal blood pressure.
  • More common in adrenal incidentalomas and those diagnosed via genetic screening.
    
    

Endocrine and Metabolic Effects

• Hyperglycemia and Insulin Resistance:
  • Due to catecholamine-induced glycogenolysis and inhibition of insulin secretion.
  • May mimic type 2 diabetes.
  • Resolves after tumor removal.
• Hypercalcemia:
  • Seen in MEN2-associated pheochromocytomas due to concurrent primary hyperparathyroidism.
• Cushing Syndrome:
  • Rare but may develop due to ectopic ACTH secretion.
    
    

Uncommon Presentations

• Cardiac Manifestations:
  • Tachyarrhythmias, atrial fibrillation, or ventricular arrhythmias.
  • Myocardial infarction-like symptoms due to catecholamine excess.
  • Catecholamine-induced cardiomyopathy, similar to Takotsubo cardiomyopathy.
• Neurological Symptoms:
  • Papilloedema (from severe, prolonged hypertension).
  • Psychiatric disturbances, including panic attacks or episodic anxiety.
• Other Rare Symptoms:
  • Fever of unknown origin.
  • Secretory diarrhea (due to ectopic vasoactive intestinal peptide (VIP) production).
    
    

Asymptomatic and Incidental Cases

• Up to 60% of cases are now diagnosed incidentally via imaging or genetic screening.
• Many tumors are detected during evaluation for:
  • Adrenal incidentalomas.
  • Family history-based genetic testing.
  • Routine biochemical screening in at-risk individuals.
    
    

Cardiovascular Findings

• Hypertension:
  • Paroxysmal (50% of cases), often triggered by stress, medications, or food.
  • Sustained hypertension is also common.
  • Normotension (5–15% of cases), particularly in those diagnosed incidentally or through genetic screening.
• Orthostatic Hypotension:
  • Caused by volume contraction due to prolonged vasoconstriction and reduced plasma volume.
• Hypertensive Retinopathy:
  • Retinal hemorrhages, exudates, papilloedema, indicating severe or chronic hypertension.
• Tachyarrhythmias:
  • Sinus tachycardia is the most common rhythm disturbance.
  • Atrial fibrillation, ventricular arrhythmias, conduction abnormalities may also be present.
• Catecholamine-induced Cardiomyopathy:
  • Reversible dilated or hypertrophic cardiomyopathy.
  • May mimic Takotsubo (stress-induced) cardiomyopathy.
  • Pulmonary oedema, which may worsen if beta-blockers are given before alpha-blockade.
    
    

Neurological Findings

• Tremors:
  • Due to adrenergic overstimulation.
• Papilloedema:
  • Caused by prolonged severe hypertension.
• Paroxysmal Anxiety and Panic-like Episodes:
  • Patients may appear restless, diaphoretic, and visibly anxious.
    
    

Metabolic and Endocrine Findings

• Weight Loss:
  • Due to increased metabolic rate and lipolysis.
• Hyperglycemia:
  • Secondary to catecholamine-induced insulin resistance.
• Hypercalcemia:
  • Seen in MEN2-associated pheochromocytomas due to concurrent primary hyperparathyroidism.
• Diaphoresis:
  • Profuse sweating during hypertensive episodes.
  • Present in 60–70% of symptomatic cases.
    
    

Gastrointestinal and Abdominal Findings

• Abdominal Mass:
  • Palpable in large pheochromocytomas or paragangliomas.
• Epigastric or Flank Pain:
  • May indicate tumor mass effect or necrosis.
• Ileus (Intestinal Paralysis):
  • Adrenergic inhibition of gut motility may result in severe constipation.
    
    

Dermatological Findings

• Pallor:
  • Episodic alpha-mediated vasoconstriction, especially during hypertensive episodes.
• Neurofibromas and Café-au-Lait Macules:
  • Found in Neurofibromatosis type 1 (NF1)-associated pheochromocytomas.
    
    

Signs of Malignancy or Metastatic Disease

• Bone pain or pathological fractures:
  • Suggests skeletal metastases.
• Hepatomegaly:
  • May indicate liver metastases.
• Lymphadenopathy:
  • Can be a sign of regional or distant spread.
• Cachexia:
  • Seen in aggressive or metastatic pheochromocytomas.
    
    

Findings in Familial Syndromes

• MEN2 (Multiple Endocrine Neoplasia type 2):
  • Thyroid nodules (medullary thyroid carcinoma).
  • Mucosal neuromas (MEN2B).
  • Marfanoid body habitus (MEN2B).
• Von Hippel-Lindau (VHL) Disease:
  • Retinal angiomas.
  • Hemangioblastomas (brain and spinal cord).
  • Pancreatic and renal cysts.
• Neurofibromatosis Type 1 (NF1):
  • Café-au-lait macules.
  • Axillary freckling.
  • Lisch nodules in the iris.
    
    

Biochemical Testing

• Primary Tests:
  • Plasma Free Metanephrines or 24-hour Urine Fractionated Metanephrines:
    • First-line test due to high sensitivity.
    • Plasma testing should be performed in the supine position.
    • Elevations three times above the upper limit of normal are diagnostic.
    • Certain medications (e.g., tricyclic antidepressants, beta-blockers, levodopa, sympathomimetics) can interfere with results.
    • Urine creatinine measurement ensures the adequacy of collection.
• Secondary Biochemical Tests:
  • Chromogranin A:
    • Secreted alongside catecholamines.
    • Elevated in pheochromocytomas and other neuroendocrine tumors.
    • Sensitivity: 83%, Specificity: 96%.
    • Used in screening for recurrence post-surgery.
  • Clonidine Suppression Test:
    • Used in borderline cases or when false positives are suspected.
    • Clonidine suppresses sympathetic neuron catecholamine release, but not tumor secretion.
    • Lack of suppression indicates pheochromocytoma.
      
      

Genetic Testing

• Recommended for all patients with pheochromocytoma to identify hereditary tumor syndromes.
• Common Gene Mutations:
  • Von Hippel-Lindau (VHL) syndrome.
  • Multiple Endocrine Neoplasia type 2 (MEN2).
  • Neurofibromatosis type 1 (NF1).
  • Succinate dehydrogenase (SDH) mutations (SDHB, SDHC, SDHD, SDHAF2).
  • MYC-associated factor X (MAX) and Hypoxia-inducible factor 2-alpha (HIF2A).
    
    

Hematological and Biochemical Markers

• Complete Blood Count (CBC):
  • Erythrocytosis may be seen due to erythropoietin overproduction.
• Serum Calcium:
  • Hypercalcemia suggests MEN2-associated pheochromocytoma.
• Serum Potassium:
  • Hypokalemia may be present due to catecholamine-induced kaliuresis.
    
    

Imaging Studies

• CT Scan (Abdomen and Pelvis):
  • First-line imaging due to high spatial resolution.
  • Detects adrenal tumors as small as 0.5 cm.
  • Inhomogeneous masses with central necrosis.
  • Attenuation >10 HU on unenhanced imaging is suggestive.
• MRI (Abdomen and Pelvis):
  • Preferred for children, pregnant women, and metastatic disease.
  • Pheochromocytomas appear hyperintense on T2-weighted images.
    
    

Functional Imaging for Metastatic or Multifocal Disease

• I-123 Metaiodobenzylguanidine (MIBG) Scintigraphy:
  • Used for:
    • Large tumors (high metastatic risk).
    • Recurrent disease.
    • Planning radiotherapy with I-131 MIBG.
  • Sensitivity and specificity: >90%.
• 18F-FDG PET (Positron Emission Tomography):
  • Used to differentiate benign vs. malignant pheochromocytomas.
  • Preferred over MIBG in metastatic disease.
  • Increased uptake in catecholamine-producing tissues.
    
    

Anxiety Disorders and Panic Attacks

• Clinical Overlap:
  • Both can present with palpitations, tremors, diaphoresis, and a sense of impending doom.
  • Panic attacks are often situational and associated with psychological triggers, whereas pheochromocytoma symptoms are episodic and independent of external stimuli.
• Key Differentiating Features:
  • Absence of biochemical evidence of catecholamine excess in anxiety disorders.
  • Normal metanephrines and catecholamines during panic episodes.
    
    

Essential or Resistant Hypertension

• Clinical Overlap:
  • Both may present with headaches, palpitations, and diaphoresis.
• Key Differentiating Features:
  • Essential hypertension is usually drug-responsive and does not present with paroxysmal symptoms.
  • Pheochromocytoma is suspected in cases of:
    • Paroxysmal hypertension.
    • Resistant hypertension despite multiple antihypertensives.
    • Hypertensive crises with catecholamine surges.
  • Metanephrine and catecholamine tests are negative in essential hypertension.
    
    

Hyperthyroidism and Thyrotoxicosis

• Clinical Overlap:
  • Diaphoresis, palpitations, tremors, weight loss, and heat intolerance are seen in both conditions.
• Key Differentiating Features:
  • Low TSH and elevated free T4/T3 in hyperthyroidism.
  • Urinary and plasma metanephrines are normal in thyroid disorders.
    
    

Illicit Substance Use (Cocaine, Amphetamines, Sympathomimetics)

• Clinical Overlap:
  • Hypertension, tachycardia, diaphoresis, anxiety, agitation, and tremors can mimic pheochromocytoma.
  • Acute catecholamine excess from drug use can cause hypertensive crises.
• Key Differentiating Features:
  • Toxicology screening for cocaine, amphetamines, and other sympathomimetics.
  • Transient elevation of catecholamines after substance use, compared to persistent elevations in pheochromocytoma.
    
    

Carcinoid Syndrome

• Clinical Overlap:
  • Both conditions cause episodic flushing, palpitations, and diarrhoea.
• Key Differentiating Features:
  • Carcinoid syndrome is associated with intense flushing and wheezing, whereas pheochromocytoma causes pallor during hypertensive crises.
  • Elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) in carcinoid syndrome.
  • Negative metanephrine and catecholamine tests in carcinoid syndrome.
    
    

Cardiac Arrhythmias

• Clinical Overlap:
  • Palpitations and tachycardia are common in both conditions.
• Key Differentiating Features:
  • ECG, Holter monitoring, and telemetry confirm arrhythmias.
  • Pheochromocytoma may trigger arrhythmias such as supraventricular tachycardia or ventricular fibrillation.
  • Normal catecholamines and metanephrines in isolated arrhythmias.
    
    

Menopause

• Clinical Overlap:
  • Hot flashes, sweating, and palpitations are common in menopausal women.
• Key Differentiating Features:
  • Menopausal symptoms occur in cycles, while pheochromocytoma attacks are episodic and may be associated with pallor.
  • Normal catecholamines and metanephrines in menopause.
    
    

Pre-eclampsia

• Clinical Overlap:
  • Hypertension, headaches, and potential hypertensive crises during pregnancy.
• Key Differentiating Features:
  • Pre-eclampsia presents after 20 weeks of gestation.
  • Associated with proteinuria and elevated uric acid (absent in pheochromocytoma).
  • Catecholamines and metanephrines elevated in pheochromocytoma, but normal in pre-eclampsia.
    
    

General Approach

• The primary treatment goal is to eliminate the adverse effects of catecholamine excess.
• Surgical resection is the definitive treatment, with medical optimisation required preoperatively.
• High-risk considerations include hypertensive crises, cardiovascular complications, and metastatic disease.
  
  

Preoperative Management

• A hypertensive crisis (systolic BP >250 mmHg) may occur:
  • At initial presentation.
  • During tumor manipulation in surgery if inadequate preoperative blockade was given.
• Immediate Treatment:
  • IV Alpha Blockade:
    • Phentolamine (competitive non-selective α-blocker).
    • Nitroprusside (vasodilator, rapid onset).
    • Nicardipine (calcium-channel blocker, titratable).
  • Adjunctive Therapy:
    • Additional oral α-blockers (e.g., doxazosin, prazosin, or phenoxybenzamine).
    • Beta-blockers only after α-blockade to prevent hypertensive crisis from unopposed α-stimulation.
      
      

• First step in medical optimisation is α-adrenergic blockade to:
  • Reduce blood pressure and prevent intraoperative hypertensive spikes.
  • Expand intravascular volume (catecholamine excess causes volume contraction).
• Preferred α-Blockers:
  • Selective α-1 Blockers: Doxazosin, Prazosin, Terazosin (shorter duration, titratable, less postoperative hypotension).
  • Non-Selective α-Blocker: Phenoxybenzamine (long-acting, more potent but causes postoperative hypotension).
• Hydration and High-Salt Diet:
  • A high-sodium diet (>5 g/day) for 7–14 days helps expand blood volume.
    
    

• Calcium Channel Blockers (CCBs):
  • Nifedipine, Amlodipine for additional BP control.
  • Can be monotherapy in patients unable to tolerate α-blockers.
• Metyrosine (Tyrosine Hydroxylase Inhibitor):
  • Blocks catecholamine synthesis (reduces production by 35-80%).
  • Used in:
    • Patients with very high catecholamine levels.
    • Metastatic or unresectable tumors.
    • Preoperatively, if severe catecholamine excess is suspected.
      
      

• Initiated 2-3 days preoperatively after α-blockade is adequate.
• Purpose:
  • Controls tachycardia and arrhythmias.
  • Prevents beta-adrenergic overstimulation during surgery.
• Caution:
  • Beta-blockers must NEVER be given before alpha-blockade as they cause unopposed α-stimulation, leading to severe hypertensive crises.
    
    

Surgical Management

• Definitive treatment for benign pheochromocytomas.
• Laparoscopic adrenalectomy (preferred for tumors ≤6 cm).
• Open adrenalectomy for:
  • Large tumors (>6 cm).
  • Suspicion of malignancy.
  • Invasive or recurrent tumors.
    
    

• Recommended in hereditary pheochromocytomas (MEN2, VHL) to preserve adrenal function.
• Reduces lifelong steroid dependence but requires long-term surveillance.
  
  

• Intraoperative Hypertensive Crises:
  • Caused by tumor manipulation.
  • Managed with:
    • IV Nitroprusside, Phentolamine, Nicardipine (short-acting antihypertensives).
• Postoperative Hypotension:
  • Loss of catecholamine vasoconstriction → Treat with IV fluids.
• Postoperative Hypoglycemia:
  • Loss of catecholamine-mediated insulin suppression → IV glucose replacement.
    
    

Management of Metastatic or Unresectable Pheochromocytoma

• Surgical removal of primary tumor and metastases if possible.
• Reduces catecholamine burden and improves symptom control.
  
  

• Used when surgery is not feasible.
• Standard regimen: Cyclophosphamide, Vincristine, Dacarbazine (CVD).
• Temozolomide (preferred in SDHB-mutated tumors).
  
  

• I-131 Metaiodobenzylguanidine (MIBG) therapy:
  • Used if MIBG scintigraphy is positive.
  • Targets catecholamine-producing cells.
• Peptide Receptor Radionuclide Therapy (PRRT):
  • 177Lu-DOTATATE (somatostatin analog therapy) in somatostatin receptor-positive tumors.
• External Beam Radiotherapy (EBRT):
  • For painful bone metastases or soft tissue metastases.
    
    

• Sunitinib (used in progressive metastatic cases).
• Hypoxia-Inducible Factor-2α (HIF2A) Inhibitors (Belzutifan).
• Immunotherapy (Pembrolizumab) in refractory cases.
  
  

Long-Term Follow-Up & Recurrence Monitoring

• Recurrence Rate:
  • 3-16% for benign tumors.
  • Can occur decades after initial surgery.
• Follow-up Tests:
  • Plasma and urine metanephrines annually.
  • Imaging every 1-2 years in high-risk cases.
• Genetic Testing:
  • Determines long-term risk and need for family screening.
    
    

Prognosis in Benign Disease

• Surgical cure rate: More than 85% of patients achieve long-term remission after adrenalectomy.
• Five-year survival: 95% in cases of benign pheochromocytoma.
• Recurrence risk:
  • Occurs in <10% of cases.
  • Hereditary tumors have a higher recurrence rate, necessitating lifelong follow-up.
• Long-term Hypertension Risk:
  • Up to 20% of patients remain hypertensive postoperatively due to chronic vascular changes from prolonged catecholamine exposure.
  • Requires long-term blood pressure monitoring and management.
    
    

Prognosis in Metastatic Disease

• No curative treatment available.
• Five-year survival: 42%.
• Long-term survival possible:
  • Some patients survive >20 years post-diagnosis.
  • Factors associated with prolonged survival:
    • Younger age at diagnosis.
    • Female sex.
    • Early diagnosis and complete tumor excision.
  • Poor prognostic factors:
    • Male sex.
    • Presence of synchronous metastases.
    • Aggressive tumor mutations.
• Tumor genetics influence prognosis:
  • Succinate dehydrogenase (SDH) gene mutations are associated with:
    • Aggressive disease.
    • Higher metastatic potential.
    • Poorer overall survival.
      
      

Recurrence Risk and Long-Term Monitoring

• Recurrence can occur in both sporadic and familial cases.
• A study of 192 patients found:
  • Higher recurrence rates in familial tumors.
  • Right adrenal and extra-adrenal tumors had greater recurrence risk.
• Meta-analysis data:
  • Recurrence rate after curative surgery: ~3%.
  • Mean follow-up: 77 months.
• Endocrine Society Guidelines:
  • Lifelong annual biochemical testing is recommended to monitor for recurrence or metastatic disease.
    
    

Cardiovascular and Neurological Complications

• Hypertension is the most common complication.
• Other cardiovascular risks:
  • Arrhythmias (e.g., atrial fibrillation, ventricular fibrillation).
  • Dilated cardiomyopathy (due to chronic catecholamine excess).
  • Pulmonary oedema (cardiogenic or non-cardiogenic).
• Neurological risks:
  • Hypertensive encephalopathy with altered mental status and seizures.
  • Stroke risk due to:
    • Cerebral infarction.
    • Thromboembolism from dilated cardiomyopathy.
    • Intracerebral haemorrhage from severe hypertension.
      
      

Prognosis in Pregnancy-Associated Pheochromocytoma

• Extremely rare (0.002% of all pregnancies).
• High maternal and fetal mortality if undiagnosed:
  • Maternal mortality: 48%.
  • Fetal mortality: 55%.
• Improved outcomes with early diagnosis:
  • Maternal mortality reduced to nearly 0%.
  • Fetal mortality decreases to 15%.
    
    

Bone and Vascular Complications

• High prevalence of osteoporosis and atherosclerosis in pheochromocytoma patients.
• Vertebral fractures strongly correlate with:
  • Abdominal aortic calcification (AAC).
  • Higher catecholamine levels.
  • Increased cardiovascular disease risk.
    
    

Acute Hypertensive Crisis

• Timeframe: Short-term
• Likelihood: High
• Triggers:
  • Drugs inhibiting catecholamine reuptake (e.g., tricyclic antidepressants, cocaine).
  • Opiates.
  • Anesthesia induction.
  • X-ray contrast media.
• Potential Consequences:
  • Cerebral hemorrhage.
  • Cardiac arrhythmias.
  • Myocardial infarction.
  • Hypertensive encephalopathy.
  • Heart failure.
• Management:
  • Immediate alpha blockade:
    • Alpha-1 blockers: Terazosin, Doxazosin, Prazosin.
    • Non-selective alpha-blocker: Phenoxybenzamine.
  • IV antihypertensive agents:
    • Nitroprusside.
    • Phentolamine.
    • Nicardipine.
  • Titrated therapy: IV agents can be combined with oral alpha-1 blockers.
    
    

Neurological Complications

• Timeframe: Short-term
• Likelihood: Medium
• Manifestations:
  • Hypertensive Encephalopathy:
    • Altered mental status.
    • Seizures.
    • Focal neurological deficits.
  • Cerebrovascular Accidents (Stroke):
    • Ischemic stroke due to catecholamine-induced vasoconstriction.
    • Embolic stroke from mural thrombi in dilated cardiomyopathy.
    • Intracerebral hemorrhage due to uncontrolled hypertension.
  • Cerebral Vasculitis:
    • Inflammatory vascular changes leading to transient ischemic attacks (TIAs) or infarction.
      
      

Cardiovascular Complications

• Timeframe: Short-term and long-term
• Likelihood: High
• Hypertensive Cardiovascular Disease:
  • Persistent hypertension leads to cardiomyopathy and hypertensive heart failure.
  • Hypertensive retinopathy with retinal hemorrhages and exudates.
• Arrhythmias:
  • Tachyarrhythmias: Atrial fibrillation, ventricular tachycardia, ventricular fibrillation.
  • Catecholamine-induced cardiomyopathy (Takotsubo-like or dilated cardiomyopathy).
  • Cardiogenic shock in severe cases.
• Myocardial Infarction:
  • Due to coronary vasospasm and catecholamine excess.
• Pulmonary Oedema:
  • Either cardiogenic (left heart failure) or noncardiogenic (capillary leak syndrome).
• Lactic Acidosis:
  • Catecholamine-induced metabolic dysfunction leading to tissue hypoxia and anaerobic metabolism.
    
    

Postoperative Complications

• Timeframe: Short-term
• Likelihood: Medium
• Hypotension:
  • Sudden drop in catecholamines after tumor removal leads to vascular relaxation.
  • Management:
    • IV fluid resuscitation.
    • Plasma expanders or inotropes (if needed).
    • Vasopressin in catecholamine-resistant hypotension.
• Arrhythmias:
  • Persistent arrhythmias post-surgery require:
    • Lidocaine or esmolol for control.
• Hypoglycemia:
  • Rebound hyperinsulinemia postoperatively leads to hypoglycemia in ~13% of patients.
  • IV glucose replacement required for management.
    
    

Renal and Gastrointestinal Complications

• Timeframe: Variable
• Likelihood: Medium
• Renal Dysfunction:
  • Acute renal failure due to hypertensive nephropathy.
  • Renal infarction from catecholamine-induced vasoconstriction.
• Gastrointestinal Complications:
  • Ischemic enterocolitis due to vasospasm of mesenteric arteries.
  • Polyuria and Polydipsia (especially in children) due to catecholamine-induced hyperglycemia and osmotic diuresis.
    
    

Psychiatric and Psychological Effects

• Timeframe: Long-term
• Likelihood: Low to medium
• Common Symptoms:
  • Anxiety and panic-like episodes.
  • Depression due to chronic adrenergic hyperactivity.
  • Postoperative psychological disturbances after long-standing catecholamine excess is eliminated.
    
    

Metabolic and Endocrine Effects

• Timeframe: Long-term
• Likelihood: Low to medium
• Chronic Hypertension and Metabolic Dysfunction:
  • Persistent hypertension even after tumor removal in ~20% of patients.
• Bone and Vascular Disease:
  • Osteoporosis and vertebral fractures due to prolonged catecholamine excess.
  • Atherosclerosis and arterial calcification associated with chronic hypertension.
    
    

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