Pheochromocytoma D35.0

Felix Fränkel 1886; the Berlin pathologist Ludwig Pick was the first to use the term pheochromocytoma in 1912.

Pheochromocytomas (from Greek phaios=dark, chroma =color) are rare, catecholamine-producing, spontaneously occurring, but also hereditary (about 25%), neuroendocrine, unilaterally (about 90%) or bilaterally localized tumors of the chromaffinous tissue of the adrenal medulla (80% of pheochromocytomas are localized in the adrenal medulla) or the extraadrenal paraganglia (seeand paragangliomas) (Farrugia FA et al. 2019). In children about 30% of tumors are located extraadrenally.

About 60% of pheochromocytomas secrete both adrenalin and noradrenalin. Extra-adrenal pheochromocytomas (these are called paragangliomas) above the diaphragm produce only norepinephrine; malignant pheochromocytomas also produce the catecholamine dopamine.

Spontaneously occurring pheochromocytomas (75%)

Hereditary phachromocytomas (25%):

• Multiple endocrine neoplasia (MEN) type 2 (mutation of the RET prooncogene)
• Von Hippel-Lindau syndrome type 2 (mutation in the VHL gene)
• Neurofibromatosis (type 1)
• Familial paraganglioma (Mutation of the genes for various mitochondrial enzymes: Up to 10% of genetically determined PCC/PGLs are caused by a germline mutation in one of the following SDHx genes: SDHD (11q23), SDHC (1q21), SDHB (1p36.1-p35), SDHA (5p15) and SDHAF2/SDH5 (11q31.1)) -see also under paragangliomas.

Incidence: < 1/100,000 per year (2-8 cases per 1 million population). The incidence(prevalence) is estimated at 0.05-0.13% in the general population and 0.1-0.5% in patients with hypertension. About 0.1% of all hypertension is caused by a pheochromocytoma.

About 25% of pheochromocytomas are hereditary and occur in the context of syndromes:

• Multiple endocrine neoplasia (MEN), type 2 (mutation of the RET protooncogene)
• von-Hippel-Lindau syndrome type 2 (mutation in the VHL gene)
• Neurofibromatosis type 1 (M. Recklinghausen; mutation of the neurofibromatosis type 1 gene)
• Familial paraganglioma (mutation of the genes for the mitochondrial enzymes SDHB, SDHC, SDHD -s.u. SDH gene); other mutations in the following genes: SDHA, SDHAF2, TMEM127, MAX

In a number of pheochromocytomas, germline or somatic mutations can be detected.

Median age in the sporadic forms 40 - 50 years, in the hereditary forms < 40 years. In a larger Spanish study of 693 unselected pheochromocytoma / paraganglioma patients, 69% of patients were diagnosed with pheochromocytoma, 15% with sympathetic paraganglioma and 22% with parasympathetic paraganglioma (Cascon A et al. 2009). A smaller proportion proved to be a mixed type.

Paroxysmal hypertension with hypertensive crises (50% in adults) or persistent hypertension (50% in adults - but 90% in children). During a hypertensive crisis, sometimes triggered by palpation of the abdomen, patients complain of headache,

Headache 70-90%, sweating (65-70%), tachycardia (50-70%), heat intolerance (40-70%), tremor (40-50%), pallor (40-45%), weight loss (35-40%), nervousness, panic and anxiety (35-40%). Angina pectoris (20-50%). During 24 h blood pressure measurement (lack of night setback). Possibly paradoxical increase in blood pressure after administration of beta-blockers.

Other findings: pale skin, hyperglycaemia and glucosuria (1/3 of normal), leucocytosis, weight loss (hypermetabolism).

Lab! If an excess of hormones is proven, imaging procedures are performed: (endo)sonography, CT and magnetic resonance imaging are suitable for imaging the adrenal region (sensitivity approx. 95% and specificity approx. 75%). In the case of extraadrenal pheochromocytomas (paragangliomas), further imaging must be performed.

In most cases, CT or MRI of the abdomen as well as scintigraphy or SPECT (single photon emission CT) with 123Iodine-MIBG (metajodo-benzylguanidine) are used. If the MIBG result is negative, a somatostatin receptor scintigraphy can also be performed if the suspected tumor is still present.

Polygonal and spindle-shaped chromaffin cells and supporting cells arranged in cell bales. Most common are cell nuclear atypes. Mostly good vascularization of the parenchyma. A malignant pheochromocytoma is only diagnosed when metastases are detected. Metastases occur in regional lymph nodes or haematogenically preferably in the liver, lungs and bones.

Sporadically occurring, therapy-resistant hypertension (-crises) with palpitations, headaches, unmotivated sweating attacks, facial pallor, 24 h blood pressure measurement (lack of night-time reduction) are suspect. Evidence of autonomous catecholamine overproduction.

Remark: A biochemical diagnosis should be made in the following patients:

• Patients with newly developed therapy-resistant hypertension, patients with paradoxical blood pressure reaction during anesthesia or surgery, patients with a hereditary predisposition to pheochromocytoma, asymptomatic patients with an incidental adrenal gland tumor, patients with sudden panic attacks.
• Note: 2 weeks before laboratory diagnosis, discontinue interfering drugs if possible (e.g. sympathomimetics, alpha-receptor blockers, antidepressants, clonidine). Diuretics, calcium antagonists, ACE inhibitors and Sartane can be left in place.
• Determination of free plasma metanephrines under strict acceptance conditions (placing a venule, at least 30 min. resting position of the patient before blood collection). A pheochromocytoma is likely to occur at single values > 3 times the norm or simultaneously elevated metanephrine and normetanephrine. Alternatively, fractionated metanephrines can be determined in acidified 24 h urine. Further determination of 3-methoxytyramine, dopamine and homovanillic acid in plasma.
• Clonidine inhibition test (prerequisite: systolic blood pressure values > 120 mmHg): After administration of clonidine, the plasma concentration of catecholamine metabolites decreases in healthy volunteers due to central inhibition of the sympathetic nervous system.

Blood pressure crises of other genesis, especially in advanced renal insufficiency; in hyperglycaemia diabetes mellitus, hyperthyroidism, cocaine or amphetamine abuse; other tumours of the adrenal gland (e.g. ganglioneuromas).

Laparoscopic tumour removal (if not possible: open surgical procedure).

For unilateral pheochromocytoma unilateral adrenalectomy. In case of MEN-2 syndrome and bilateral tumors, bilateral subtotal (organ preserving) adrenalectomy (lifelong substitution with glucocorticoids is avoided!)

At least one week before the procedure, a lowering of blood pressure is started with an alpha-blocker (e.g. phenoxybenzamine). Afterwards, an unselective beta-blocker is added. This therapeutic approach should take place, as larger amounts of catecholamines are released during surgical removal of the tumours (Naranjo J et al. 2017). Otherwise conservative therapy: therapy of a hypertensive crisis.

In case of inoperability: long-term therapy with alpha-blockers (phenoxybenzamine, prazosin).

In case of metastatic pheochromocytoma (detection of 123J-MIBG-positive metastases): 131J-MIBG therapy (response rate approx. 25%); otherwise the following therapy options exist: chemo-embolization of liver metastases, palliative chemotherapy.

In case of a unilateral pheochromocytoma: complete extirpation of the affected adrenal gland.

In the presence of MEN syndrome, only the adrenal medulla is removed bilaterally. Catecholamine levels and blood pressure return to normal in 80% of patients postoperatively.

In case of metastasis, systemic radionuclide therapy, also called endoradiotherapy (MIBG therapy = metaiod benzylguanidine, the radionuclide=131 J, a predominant β radiator) or polychemotherapy is performed.

Alternative: Phase II study with the multityrosine kinase inhibitor sunitinib.

90% of adrenal pheochromocytomas are benign,.

10% of adrenal pheochromocytomas are malignant

In extraadrenal tumours (see below paragangliomas) about 30 % are malignant.

> 50 % of patients with benign pheochromocytoma become normotensive after surgery, in the remaining cases there is also essential hypertension. In the long term, about 15 % of the patients show a recurrence; therefore control examinations are indicated.

A pheochromocytoma can also originate from the sympathetic border strand (parallel to the spinal column or major blood vessels) and is then called extra-adrenal pheochromocytoma or paraganglioma.

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