Metastatic Paraganglioma

Metastatic paraganglioma is a paraganglioma (extra-adrenal catecholamine producing or non-functional tumour of sympathetic or parasympathetic paraganglia) with metastasis to sites where chromaffin tissue is normally absent, such as bone, lymph nodes, liver and lung. Any paraganglioma can metastasise, and there is no reliable histological marker of behaviour.

Paragangliomas and phaeochromocytomas have an annual incidence of about 2 to 8 cases in 1,000,000 people. Metastases occur in about 10% to 15% of phaeochromocytomas and 20% to 30% of sympathetic paragangliomas. Median age at diagnosis is the 40s, and the sexes are equal.

More than 40% are hereditary. The main susceptibility genes are SDHB (with the highest metastatic risk, 30% to 70% for abdominal or thoracic paragangliomas), SDHA, SDHC, SDHD, SDHAF2, FH, VHL, RET, NF1, MAX, TMEM127 and HIF2A. SDHD and SDHAF2 are paternally inherited.

Pathophysiology. SDH loss causes succinate accumulation, pseudohypoxia and stabilisation of hypoxia inducible factors, with a catecholamine poor, dopamine- or noradrenaline secreting phenotype. Tumours often secrete methoxytyramine (dopamine metabolite), a marker of metastatic risk.

Prognostic features. SDHB variant, large primary tumour (over 5 cm), extra-adrenal site, high methoxytyramine, younger age and synchronous metastasis predict aggressive disease. Five year survival is about 40% to 85%, with a very variable course.

• Hypertension (sustained or paroxysmal), headache, palpitations and sweating (the classic triad), pallor, anxiety, tremor and weight loss, from catecholamine excess.
• Hypertensive crisis, arrhythmia, stroke, myocardial infarction, catecholamine cardiomyopathy or pulmonary oedema, sometimes triggered by surgery, anaesthesia, anaesthetic agents, glucocorticoids, opioids, beta blockers without alpha blockade, or tumour manipulation.
• Mass effects and bone pain from metastases, spinal cord compression, and hepatic or pulmonary symptoms.
• Head and neck parasympathetic paragangliomas (carotid body, glomus jugulare): neck mass, pulsatile tinnitus, hearing loss, cranial nerve palsies, usually non-functional.

Red flags.

• Hypertensive crisis, severe headache, chest pain or acute pulmonary oedema.
• Cord compression from vertebral metastasis.
• Any procedure, biopsy or anaesthesia in a patient with an untreated secreting tumour.

• Plasma free metanephrines (supine sampling) or 24-hour urinary fractionated metanephrines, plus 3-methoxytyramine. Interfering drugs (paracetamol with some assays, tricyclic antidepressants, labetalol, sympathomimetics) are reviewed.
• Imaging: CT or MRI of the neck, chest, abdomen and pelvis with contrast (MRI preferred for skull base and spinal disease). Functional imaging with 68Ga-DOTATATE PET-CT (preferred for metastatic disease and SDHx), FDG-PET (higher sensitivity in SDHB) and MIBG scintigraphy to select patients for radionuclide therapy.
• Pathology: chromogranin A and synaptophysin positive, with sustentacular cells (S100), and SDHB immunohistochemistry (loss in SDH-related tumours). Metastasis is defined by disease at non-chromaffin sites, not by histological features.
• Genetic counselling and germline testing for all patients (SDHx, VHL, RET, NF1, MAX, TMEM127, FH, HIF2A), with family cascade testing.
• Echocardiography, ECG, creatinine, glucose, and calcium and parathyroid hormone when MEN2 is possible.

Differential diagnosis.

• Phaeochromocytoma and non-functional neuroendocrine tumours
• Other neuroendocrine tumours metastasising to bone or liver
• Medullary thyroid carcinoma and ganglioneuroblastoma
• Renal and other hypervascular tumours metastasising to bone
• Hyperthyroidism, panic disorder and drug induced hypertension (for secretory symptoms)

Treatment is multidisciplinary. Surgery of the primary tumour and accessible metastases, and local ablation or radiotherapy of metastases, are used where possible. Cure is rarely achieved, so the aims are control of catecholamine effects and tumour growth.

Preparation before any procedure, anaesthesia, biopsy or chemotherapy in a secreting tumour.

• Alpha blockade for at least 7 to 14 days: phenoxybenzamine 10 mg orally twice daily, increased by 10 to 20 mg every 2 to 3 days to a usual 20 to 100 mg daily, for 7 to 14 days before any surgery or invasive procedure; maximum 1 mg/kg daily; monitoring: seated and standing blood pressure and heart rate (target seated blood pressure under 130/80 mmHg with standing systolic over 90 mmHg), nasal congestion, fatigue, oedema; adjustment: reduce for orthostatic hypotension, switch to a selective alpha-1 blocker if not tolerated, encourage a high salt diet and fluids and give intravenous fluids the evening before surgery
• Beta blockade only after alpha blockade is established: propranolol 10 to 20 mg orally three times daily, started only after at least 3 days of effective alpha blockade and increased to a seated heart rate of 60 to 80 beats/min; maximum 160 mg daily in this indication; monitoring: heart rate, blood pressure, signs of pulmonary oedema, glucose; adjustment: avoid in asthma, severe heart failure and second or third degree heart block, stop and review alpha blockade if hypertension worsens

Surgery and local therapy. Resection of the primary tumour and debulking of metastases when feasible, with intraoperative haemodynamic management by an experienced anaesthetist. Radiotherapy (external beam or stereotactic) for bone, spinal and symptomatic metastases. Embolisation, radiofrequency or cryoablation for liver and bone lesions.

Systemic therapy for progressive or symptomatic metastatic disease.

• Belzutifan (HIF-2 alpha inhibitor): belzutifan 120 mg orally once daily until progression or unacceptable toxicity; maximum 120 mg daily; monitoring: haemoglobin before starting and regularly (anaemia is common), oxygen saturation (hypoxia), pregnancy test; adjustment: hold for grade 3 anaemia (haemoglobin under 8 g/dL) or hypoxia and resume at a lower dose or stop, avoid in pregnancy and use non-hormonal contraception because hormonal methods may fail, no adjustment for mild renal or hepatic impairment
• Cyclophosphamide, vincristine and dacarbazine: cyclophosphamide 750 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV (maximum 2 mg) on day 1 and dacarbazine 600 mg/m2 IV daily on days 1 and 2, every 21 to 28 days for 6 to 8 cycles with alpha blockade in place; maximum cyclophosphamide 750 mg/m2 and vincristine 2 mg each cycle; monitoring: blood pressure during infusions (catecholamine surge), FBC, liver tests, creatinine, neuropathy; adjustment: reduce vincristine by 50% when bilirubin is 26 to 51 micromol/L and avoid it over 51 micromol/L, reduce cyclophosphamide when eGFR is under 30 mL/min/1.73 m2, reduce dacarbazine in renal or hepatic impairment
• Lutetium dotatate (somatostatin receptor positive tumours): lutetium (177Lu) dotatate 7.4 GBq IV over 30 minutes every 8 weeks for 4 doses, with an amino acid infusion for renal protection starting 30 minutes before; maximum 4 doses; monitoring: FBC, creatinine and liver tests before each dose, delayed myelodysplasia; adjustment: withhold for grade 2 or worse toxicity and resume at 3.7 GBq, avoid when creatinine clearance is under 30 mL/min, use contraception during and for 7 months after treatment (4 months for men)
• Sunitinib (alternative targeted therapy): sunitinib 37.5 mg orally once daily continuously until progression or unacceptable toxicity; maximum 50 mg daily; monitoring: blood pressure at each visit, liver tests, thyroid function, FBC, left ventricular ejection fraction, QTc, hand foot skin reaction; adjustment: reduce in 12.5 mg steps (to 25 mg then 12.5 mg), reduce to 25 mg daily with strong CYP3A4 inhibitors, hold for grade 3 to 4 toxicity or ejection fraction fall, stop for hepatotoxicity with ALT over 3 times the upper limit and bilirubin raised
• Radiolabelled MIBG therapy is available in some centres for MIBG-avid disease.

Hypertension and cardiovascular care. Alpha blockade continues in non-operated patients, with metyrosine used in selected centres to lower catecholamine synthesis. Avoid beta blockade without alpha blockade, and avoid glucocorticoids, metoclopramide, tricyclic antidepressants and sympathomimetics.

Monitoring. Plasma or urinary metanephrines and methoxytyramine every 3 to 6 months, with imaging every 3 to 6 months. Lifelong follow up because recurrence and metastasis can occur 10 or more years later. Annual screening for other syndrome related tumours.

Referral and escalation.

• Referral to an endocrine tumour centre on suspicion, before any surgery or biopsy.
• Emergency admission for hypertensive crisis, acute pulmonary oedema or cord compression.

Special groups.

• Pregnancy: alpha blockade with adequate fluid, with surgery in the second trimester or delivery by caesarean section at term, in a specialist centre.
• Hereditary disease: genetic counselling, cascade testing and surveillance of carriers.
• Cardiac or renal impairment: individualised fluid and drug choices.