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 tumours.
• Typically exhibit paternal imprinting.

SDHB Mutations

• Increase risk of carotid body tumours, 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 tumour 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 tumours secrete catecholamines, primarily norepinephrine and epinephrine, with some tumours 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:
  • Tyrosine hydroxylase catalyses the conversion of tyrosine to dihydroxyphenylalanine (DOPA).
  • DOPA decarboxylase converts DOPA into dopamine.
  • Dopamine β-hydroxylase converts dopamine to norepinephrine.
  • 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 Tumour 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 tumours predominantly produce norepinephrine.
• MEN 2 and NF1-associated tumours secrete both epinephrine and norepinephrine.
• SDHB/SDHD mutation-related tumours 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:
  • Anaesthesia 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 hyperglycaemia 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 tumours.

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.
• Tumours secreting vasoactive intestinal peptide (VIP) can cause watery diarrhoea.

Tumour Size and Secretory Activity

• A retrospective study found a direct correlation between tumour size and catecholamine levels:
  • Tumours ≥2.3 cm in diameter produce catecholamine/metanephrine levels three times the upper limit of normal.
  • Larger tumours are associated with greater haemodynamic 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

• Tumour 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 tumour 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

• 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, or 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

Hypertensive Crisis 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.

Preoperative Alpha Blockade

• 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.

Adjunctive Medications

• 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 tumours.
    • Preoperatively, if severe catecholamine excess is suspected.

Beta Blockade (After Alpha Blockade)

• 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

Surgical Resection

• 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

Partial (Cortical-Sparing) Adrenalectomy

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

Perioperative Risks

• 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

Debulking Surgery

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

Chemotherapy

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

Radiotherapy

• 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.

Tyrosine Kinase Inhibitors & Immunotherapy

• 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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