An interesting case of paraganglioma

A 36-year-old woman was admitted under gynaecology services with a case of Bartholin abscess. She had a past history of type 2 diabetes and hypertension. During admission she was investigated for uncontrolled blood pressure and diagnosed as having a paraganglioma. Her blood pressure was controlled on α and β blockers and she underwent operation without complications.

Phaeochromocytomas and paragangliomas are rare neuroendocrine tumours with highly variable clinical presentation, but they most commonly present as spells of headaches, sweating, palpitations and hypertension. Patients with phaeochromocytoma may develop complicated and potentially lethal cardiovascular and other complications, especially in the setting of diagnostic or interventional procedures (eg, upon induction of anaesthesia or during surgery). The serious and potentially lethal nature of such complications is due to the potent effect of paroxysmal release of catecholamines. Because this warrants prompt diagnosis and treatment, the doctor should be aware of the clinical manifestations and complications of catecholamine excess and be able to provide proper preoperative management to minimise catecholamine-related preoperative, intraoperative and postoperative adverse events. The following clinical scenario and discussion aim to enhance the knowledge of doctors regarding the behaviour of phaeochromocytoma, and to outline current approaches to comprehensive preoperative management of patients with this tumour.

CASE PRESENTATION

The patient was admitted under gynaecology service for management of a Bartholin abscess. She was referred for medical consultation for uncontrolled blood pressure, which ranged from 180 to 240 mm Hg systolic and 110 to 140 mm Hg diastolic. On direct questioning she admitted to having had episodic headaches, palpitations, sweating and panic attacks. She had no history of weight loss, shortness of breath, menstrual disorders or visual problems.

She has no family history of hypertension or diabetes. She is a married housewife, non-smoker and non-alcoholic with no particular concerns. She had no significant past medical or surgical history. Her medication profile was as follows: amlodipine 5 mg daily, valsartan 160 mg daily, metformin 1000 mg twice a day, glicliazide 90 mg daily, pravastatin 40 mg daily and isophane insulin 16 units subcutaneous twice daily.

INVESTIGATIONS

Laboratory investigations were serum sodium 135 mmol/litre (normal range 135–145), serum potassium 3.7 mmol/litre (3.5–5.1), serum chloride 105 mmol/litre (98–107), serum urea 64 mg/dl (10–50), serum creatinine 1.20 mg/dl (0.7–1.4), blood glucose 274 mg/dl (70–110), serum calcium 10.3 mg/dl (8.4–10.2), serum phosphorus 3.3 mg/dl (2.7–4.5) and HbA1c 8.9.

The 24 h urine test for catecholamine gave a total urine volume of 1800 ml. Noradrenalin was 16 969 nmol/24 h (160–485), 2868 μg/24 h (27–81), adrenaline <27 nmol/24 h (27–165), <5 μg/24 h (4–90), dopamine 1818 nmol/24 h (1300–3000), 278 μg/24 h (198–459).

MRI of the abdomen showed a well defined round, solid, retroperitoneal mass with an area of necrosis in the retrocaval and right para-aortic area close to right hilum. The mass was hypointense on T2-weighted and short tau inversion recovery (STIR) sequences and measured approximately 4 × 4 × 3.6 cm. No mass was detected on left side. The adrenals were normal in size and signal intensity. No suprarenal mass was detected. Liver, spleen, pancreas and kidneys were normal with no ascites.

A metaiodobenzyl guanidine (MIBG) scan showed an area of patchy activity below the liver. No other significant abnormal activity could be seen.

Clinical course

Blood pressure was well controlled by addition of the α blocker trazosin (2 mg daily) and later on the β blocker bisoprolol (5 mg daily). The patient’s blood sugar was well maintained with the above medications. Before operation she received a bolus of phentolamin 20 mg. During the operation an extra-adrenal mass was resected at the angle of the renal vein entering the caveat. On reviewing the specimen notes and slides, there is no area of necrosis, and we think that what appeared as area of necrosis in the MRI is due to the presence of large cystic spaces within the neoplasm (fig 1).

Figure 1.

A. The tumour is surrounded by thick fibrous capsule (arrow) (H&E stain). B. The tumour consists of clusters of large polygonal cells with large nuclei, prominent nucleoli and abundant cytoplasm, and surrounded by thin capillary network forming a neuroendocrine organoid pattern. C. Large cystic areas are seen within the tumour (arrow). D. I¹³¹ metaiodobenzyl guanidine (MIBG) scan: area of patchy activity was noted below the liver. No other significant activity could be seen.

Postoperatively the patient’s blood pressure and blood sugar were within normal ranges without medication, and her antihypertensive and diabetes medications were gradually tapered and discontinued. She was offered genetic testing but this was refused.

DISCUSSION

Essential hypertension is the most common cause of hypertension in adults, and it is a diagnosis of exclusion. The incidence of secondary hypertension varies from 2% to 10%. Phaeochromocytoma accounts for less than 0.2% cases of hypertension.^1,2 Catecholamine-secreting tumours arise from the chromaffin cells of adrenal medulla in 80% to 85% of cases and from extra-adrenal sympathetic tissues in 15% to 20% of cases (paraganglioma).^3,4 Phaeochromocytoma in adults secrete mainly noradrenaline. Dopamine-secreting tumours are increasingly being recognised, but are frequently not associated with high blood pressure. The distinction between adrenal and extra-adrenal tumours is an important one because of implications for associated neoplasms, risk of malignancy and need for genetic testing. With widespread use of CT scan, a number of asymptomatic cases of phaeochromocytoma are being discovered.^5–7

The classic triad of phaeochromocytoma consists of episodic headache, sweating and tachycardia.^1,8 About half of cases have paroxysmal hypertension, while the rest appear to have essential hypertension. Not all patients have classic symptoms.^5,9 Sustained or paroxysmal hypertension is the most common sign of phaeochromocytoma, but 5% to 15% have normal blood pressure. Other signs and symptoms that may occur include pallor, orthostatic hypotension, polyuria, polydipsia, visual blurring, hyperglycaemia, leukocytosis and papilloedema. Hyperglycaemia (type 2 diabetes) may occur due to increase catecholamine secretion, and this disappears after removal of the tumour. Phaeochromocytoma should be strongly suspected when the patient has a triad of symptoms as mentioned above, in cases of resistant hypertension, hypertension in the young (age <30 years), hypertension and diabetes, a family history of phaeochromocytoma and familial syndromes (multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type1 and von Hippel–Lindau syndrome).

The diagnosis is typically confirmed by measurement of urinary and plasma metanephrines and catecholamine, however there is still no consensus as to which is the best test.^10–12 Metanephrine is considered to be superior by some investigators.¹¹ Sensitivity is highest for plasma and urinary metanephrines (97% to 99%), while specificity is highest for vanillymandellic acid (95%) followed by total urinary metanephrines (93%). Biochemical confirmation should be followed by radiological investigation. CT and MRI are equally useful in detecting phaeochromocytoma, although MRI is more likely to detect tumours less than 0.1 cm in diameter. T2-weighed MRI with gadolinium enhancement is more sensitive for detection of extra-adrenal tumours. If abdominal CT and MRI are negative after biochemical confirmation then a MIBG scan should be considered. Other indications are large tumour (eg, >10 cm) and paraganglioma (increased risk of malignancy and metastases). A MIBG scan is not indicated in cases of solitary adrenal phaeochromocytoma identified on MRI or CT scan.¹³

Management of phaeochromocytoma is via surgery; operating on a phaeochromocytoma is a high-risk procedure and an experienced surgeon and anaesthetist are required for it. Medical management consists of controlling hypertension and volume expansion before and during surgery. Surgical mortality is high due to hypertensive crisis and multiorgan failure.¹⁴ All patients should be placed on α blockers and after few days when α blockage is achieved, β blockers should be introduced slowly. Phenoxybenzamine is considered as the drug of first choice; alternatives are selective α₁ blockers (prazosin, terazosin and doxazosin), especially when long-term treatment is indicated (metastatic carcinoma). Calcium channel blockers have also been utilised. Although there is less experience with calcium channel blockers than α and β blockers, calcium channel blockers may be as effective^15,16

Paragangliomas are extra-adrenal tumours that are approximately 10% to 15% of catecholamine secreting tumours. About 10% of catecholamine secreting tumours are malignant.^17,18 Malignant phaeochromocytoma is histologically and biochemically similar to the benign form; the only clue to the potential malignancy is local or distant metastases, which may occur even 20 years after resection.^18,19 The metastases are detected by I¹³¹ MIBG scan and other imaging procedures. Phaeochromocytomas are associated with paraneoplastic syndromes. These include polycythaemia, hyperthermia and hypercalcaemia in the absence of parathyroid hormone hypersecretion.²⁰ Malignant phaeochromocytoma has a variable course with survival varying from months to decades.²⁰

The European Network for Study of Adrenal Tumours (ENS@T) working group for phaeochromocytoma recommends the provision of genetic testing and genetic counselling for all patients of phaeochromocytoma and paragangliomas. It has recently been shown that in 25% of cases, phaeochromocytoma and functional paragangliomas may be inherited.^21,22 All patients should be offered screening for von Hippel–Lindau syndrome and succinate dehydrogenase complex subunit B (SDHB) mutations in the first instance and, if no such mutations are detected, patients should be offered screening for SDHD mutations. Genetic testing should be offered especially to families at high risk. Blood should be collected after appropriate counselling and informed consent has been obtained.

LEARNING POINTS

• Young patients with hypertension should be screened for secondary hypertension.

• Preparation before surgery with proper control of blood pressure is recommended.

• Family screening with genetic studies is recommended in all cases of paragangliomas and phaeochromocytoma.