FECHROMOCYTOMA: causes, symptoms and therapy


Pheochromocytoma is a catecholamine-producing tumor (adrenaline and noradrenaline) and is a rare cause of hypertension: however, its recognition is extremely important as the disease is susceptible to resolutive surgical therapy. It is a tumor involving cells of neuroectodermal derivation, that is, coming from the neural crest; some of these, during embryonic development, undergo migration in different parts of the body, where they constitute areas of chromaffin tissue (so-called because of its affinity for chromium salts).

These cells are found mainly in the adrenal medulla, but also at the level of the paragangli, structures located near the ganglia of the autonomic vegetative system: these are generally very small areas, which however in some locations, for example in correspondence with the mesenteric artery superior or some sympathetic branches, can give rise, in the course of embryonic development or the first years of life, to larger accumulations, such as the so-called Zuckerkandl organ, normally destined for atrophy.

Tissue of this type is also found in certain sensitive areas of the arterial system, such as the carotid glomus; but there can be chromaffin islands, often very small, in the most diverse locations. Tumor growth can occur from any of these nuclei; in 90% of cases the tumor is localized in the adrenal medulla, in 10% in the paraganglia, heart, bladder, prostate, ovaries. In the latter cases, the tumor is also called paraganglioma. The peculiarity of these tumors is that they maintain the ability to secrete catecholamines (adrenaline and noradrenaline) starting from the tyrosine substrate, and therefore to induce a stimulation of the alpha and beta-adrenergic receptors.

The exceptions are paragangliomas derived from the parasympathetic ganglia of the head and neck, which are not chromaffin and are often not functional, posing only problems of expanding mass. These tumors, often located in the carotid body and glomus, are also called chemodectomas. The prevalence of secretion of one or the other substance varies from tumor to tumor: in general, adrenal tumors produce adrenaline more frequently, since the cells of the adrenal medulla are more easily supplied with the methylating enzyme necessary to convert the norepinephrine into adrenaline. In this case, however, the associated secretion of adrenaline and noradrenaline is usual, while the prevalence or secretion of adrenaline alone is exceptional. On the other hand, extrasadrenal tumors produce norepinephrine more easily.

The secretion of one or the other amine, as we will see later, conditions the symptoms and some of the characteristics of the blood pressure trend. The feedback, at the anatomical table, of pheochromocytomas it is estimated at around 1 case in 1000, higher than the clinical frequency of the disease which is around 0.1% in the hypertensive population. While in most cases it is a single benign adrenal neoformation, in 10% of cases we are faced with a malignant form, in 10% with an extra adrenal form and in another 10% with bilateral or multiple neoformations.

Causes of pheochromocytoma

Since these are cancers, the etiology is unknown. In a minority of patients, however, hereditary influences are present: in fact, a number of pheochromocytomas occur as part of complex hereditary disorders, transmitted as an autosomal dominant trait with high penetrance. In the 66% of the latter it is an isolated pheochromocytoma, rather commonly multiple or malignant. Otherwise, pheochromocytoma can occur in the context of a condition called multiple endocrine neoplasia (and commonly abbreviated to MEN, Multiple Endocrine Neoplasia from the initials of the name of the disease in English), characterized by the simultaneous presence of several endocrine tumors.

Pheochromocytoma also occurs in 10% of cases of neurofibromatosis, an always hereditary condition characterized by the presence of numerous fibroids and neuromas, especially evident in the skin. Among the forms of pheochromocytoma transmitted hereditary, lastly we remember the association with von Hippel-Lindau disease (vascular malformations of the retina and cerebellum). Recently, important advances have been made in identifying the genes that affect a predisposition to pheochromocytoma and paragangliomas. In fact, four genes have been identified that predispose to these tumors.

The first, called RET, is a proto-oncogene which, if subject to a mutation that activates it, causes a constitutive activation of the receptor tyrosine kinase. Consequently, the parafollicular cells of the thyroid that produce calcitonin and the chromaffin cells of the adrenal medulla undergo hyperplasia with a high frequency of subsequent neoplastic transformation. Mutations in the RET gene are associated with a particular variant of MEN (Multiple Endocrine Neoplasia), called MEN-2 (and distinguished in a MEN-2A which combines medullary thyroid carcinoma and hyperparathyroidism and in a MEN-2B, in the which also have a particular constitutional habit, called marfanoid (2), and multiple neuromas on the mucous membranes).

In this case the probability of developing a pheochromocytoma is about 50%. The second gene, called VHL, is a tumor suppressor gene which, if inactivated by a mutation, tends to cause von Hippel-Lindau syndrome which, as already mentioned, is characterized by retinal and central nervous system hemangiomas ( but also from the propensity to develop pancreatic and renal cysts and renal carcinomas). In this case the risk of developing a pheochromocytoma is 10-20%. Finally, more recently, two other genes have been identified, called SDHD and SDHB which, if mutated, predispose to the development of carotid body tumors. Neurofibromatosis is not dependent on mutations in any of these four genes and the frequency of its association with pheochromocytoma is low (around 1%). The general idea is that pheochromocytoma, when sporadic and without a family history, depends on a somatic mutation of one of the predisposing genes and in other cases on a mutation in the germline.

In the past it was claimed that the alterations in the germline, conditioning the onset of pheochromocytoma in the context of complex hereditary disorders, were present in the 10% of cases of this disease. A recent investigation carried out in a large cohort of apparently sporadic pheochromocytoma cases (Neumann et al., 2002, cited by Dluhy, 2002) has instead shown that about 25% of the cases studied had a mutation in the germline of one of the four susceptibility genes. The fact that the cases studied apparently had no signs of the complex diseases associated with these mutations is not surprising, as their manifestation can be partial, late or even completely missing. However, the lesson from this study is that when a pheochromocytoma is encountered, a clinical study will always be appropriate, even with particular investigations in search of possibly associated conditions and that these should be extended to family members. In the future, a genetic analysis will in any case be appropriate in these patients.

Pathophysiology of pheochromocytoma.

The clinical signs of the disease are determined by the production of catecholamines, adrenaline and / or noradrenaline by the tumor. Noradrenaline has a prevalent activity on alpha-adrenergic receptors and its action on the cardiovascular system is basically reflected in a constriction at the level of the arterioles, with a consequent reduction in the average arteriolar radius and an increase in blood pressure. Adrenaline acts on both alpha and beta -adrenergic receptors. The stimulation of the latter causes a vasodilation of the muscular arterioles, with an antihypertensive effect.

However, adrenaline plays an important action in the heart, as the activation of beta-adrenergic receptors in this site causes an increase in the frequency and strength of contraction of the heart, with significant effects on blood pressure levels. The prevalence of secretion of one or the other sympathetic amine therefore conditions the symptoms reported by the patient. Often the release of catecholamines into the blood (see below) can have exceptional increases and hypertension can be episodic.

When it is secreted above all adrenaline, may occur, at the same time as the pressure increase, crises of malaise characterized by vasomotor phenomena, sweating, headache, tachycardia, fine tremors and feelings of anxiety or distress (the latter effects are due to the action of adrenaline on the central nervous system) . In some cases, orthostatic hypotension may occur alongside or instead of hypertensive episodes.

This can occur in the case of tumors that produce very large quantities of adrenaline, due to a peripheral action that is contrary to hypertension, and an extreme tachycardia that conditions a decrease in cardiac output, due to a reduction in diastolic filling time. Hypotensive episodes can also occur following so-called “catecholaminic storms”, paroxysmal releases of high quantities of these hormones, as a consequence of hemorrhagic necrosis in the context of a pheochromocytoma. In such cases cardiocirculatory phenomena may be particularly evident due to a direct damaging action of catecholamines in extreme excess on myocardial cells, and perhaps also to their action increasing the permeability of the endothelial cells of the pulmonary circulation.

Clinical manifestations and symptoms of pheochromocytoma.

A peculiarity of pheochromocytomas is linked to the fact that, at least in half of the cases, the secretion of the vasoactive amines does not occur with a constant flow, but there is a storage of the substances inside the tumor cells, with the disposal of large quantities in certain circumstances. The stimulus to the release of catecholamines, which obviously corresponds to a symptomatology with a typically paroxysmal trend, is generally constituted by an increase in intra-abdominal pressure: the bending of the bust, sneezing, rice crises, a large meal, defecation efforts or the same urination (this is the case of the very rare bladder pheochromocytomas; however the effort of urination can cause the withdrawal of catecholamines even from sites other than the bladder) can trigger the hypertensive crisis.

Sometimes a simple urography or even a deep palpation of the abdomen may be sufficient. In some cases, however, crises can appear without a clear trigger; they can be rare, with episodes several months apart, or frequent, several times a day. The duration varies from a few minutes to a few hours, but in general these are never particularly long periods; there is often a tendency to increase in frequency with the passage of time.

The pressure trend can take different forms. In about 25% of cases the pressure usually remains at normal levels, and hypertensive episodes are inserted on these at more or less close intervals. In about 30% of patients with pheochromocytoma, blood pressure values are persistently elevated and paroxysmal hypertensive episodes are added to this underlying hypertension. Finally, in another 30% of patients, stable hypertension is found, without paroxysmal seizures. Another 15% has a completely irregular blood pressure trend. It is therefore important to note that, if in a certain number of cases patients appear to be normotensive outside the critical periods (and it is therefore right to consider the hypothesis of pheochromocytoma in the face of paroxysmal hypertensive episodes), most patients present constantly high blood pressure levels and some of them never have hypertensive crises. From the clinical point of view, the patient can be completely asymptomatic, although this occurrence is rare, and mainly related to forms secreting only continuous flow norepinephrine.

In general, however, pheochromocytoma involves a form of hypertension more commonly linked to symptoms, and the cardinal ones are made up of headache, profuse sweating, heartbeat; to these can be added, particularly in the forms secreting adrenaline, feelings of anguish and tremors. Angina-like symptoms may occur in older patients. During the visit, in addition to the detection of often significantly elevated blood pressure values, one can observe the presence of thinness, sweating, state of extreme anxiety, with dilated pupils, tremors. It is also important to look for signs of polyendocrinopathies and any abnormalities such as neurofibromas in these patients. More rarely, the patient presents with the symptoms and signs of dilated or hypertrophic cardiomyopathy (Chap. 8) and the picture may constitute a medical emergency, for acute episodes of hypotension, accompanied by extreme tachycardia and pulmonary edema. The causes of these cardiocirculatory phenomena have been illustrated in terms of physiopathology.

Pheochromocytoma Diagnosis

The presence of paroxysmal blood pressure is an element in favor of the diagnosis of pheochromocytoma, but does not give certainty. For this purpose it is necessary to carry out laboratory and instrumental investigations. Up to a few years
Triggering and / or suppression tests were used, the principle of which consists in administering substances capable of triggering or blocking hypertensive crises. Among the first are histamine, which causes a sudden release of catecholamines, tyramine or glucagon. These tests have now completely fallen into disuse as they are not without danger for the patient.

An inhibition of the action of vasoactive amines can be obtained by administering drugs capable of blocking sympathetic receptors: in patients with pheochromocytoma a drug of this type should lead to a reduction in blood pressure. For this purpose, phentolamine is usually used, a blocker: the test is considered positive if after administration a reduction in the values of the systolic pressure of 35 mmHg and of the diastolic pressure of 25 mmHg is obtained. However, it must be considered that this test can give up to a 25% of false positives and that it is suitable for the evaluation of patients with underlying hypertension only.

The safest method is to measure catecholamines and their metabolites in the blood and urine (Fig. 1.3). In the urine, adrenaline and noradrenaline, metanephrine and normetanephrine and vanilmandelic acid can be measured. Most of the catecholamines are excreted in the metabolized urine: adrenaline and norepinephrine are found in quantities of the order of micrograms, while vanilmandelic acid is in the order of milligrams, therefore its dosage is much easier. The evaluation of amino derivatives after a hypertensive crisis is particularly useful; therefore it is advisable to start urine collection for 24 h immediately after a paroxysmal episode. The only drawback related to this test is that many substances are able to modify the urinary levels of vanilmandelic acid, and among these first of all many foods containing vanillin, such as sweets, tea, coffee, various fruits (citrus fruits, bananas) in addition to countless drugs. Some particularly equipped laboratories are able to perform the dosage of adrenaline and noradrenaline in the plasma.
Once an increase in the levels of catecholamines has been ascertained, the problem of the localization of the pheochromocytoma arises: this is quite simple if the neoformation is found in the adrenal gland, which happens approximately in 90% of cases; ultrasonography is a bloodless instrumental examination, however capable of highlighting neoformations of moderate size. An analogous argument can be made with regard to computerized axial tomography. Arteriography allows the visualization of circulatory abnormalities of the affected adrenal gland; a venous catheterization, in expert hands, allows selective dosages of catecholamines in different regions, useful above all in the suspicion of extra adrenal pheochromocytomas.

These maneuvers are not entirely risk-free, as they can themselves trigger a hypertensive crisis. Therefore, a pharmacological blockade of the alpha-adrenergic receptors is usually practiced concomitantly.

Prognosis and therapy of pheochromocytoma

The disease is amenable to radical surgical treatment with a 5-year median survival of more than 95% for benign forms. In about 75% of these patients, the intervention involves a restoration of blood pressure values to normal. Alternatively, the disease leads to all the consequences of arterial hypertension on the target organs; in addition there is the risk of extremely dangerous and sometimes fatal hypertensive episodes.

In 95% of cases it is a benign heteroformation, however the diagnosis of malignancy cannot be established except a posteriori, in relation to the tendency or not to metastasize. The malignant forms are more common in extra-adrenal neoplasms and affect the loco-regional lymph nodes, therefore the skeleton, liver, lungs, central nervous system. The prognosis of malignant forms is variable and, if in the past it was described as particularly poor, cases with longer survival have recently been reported.


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