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PubMed2000

Malignant pheochromocytoma. Chromaffin granule transmitters and response to treatment.

Chromaffin granule transmitters such as chromogranin A and catecholamines have been used in the diagnosis of pheochromocytoma, but the diagnostic and prognostic value of chromogranin A have not been explored in malignant pheochromocytoma. We evaluated these transmitters in patients with pheochromocytoma (n=27), both benign (n=13) and malignant (n=14). Patients with benign pheochromocytoma were studied before and after surgical excision (n=6), whereas patients with malignant pheochromocytoma were evaluated before and after combination chemotherapy with regular cycles of cyclophosphamide/dacarbazine/vincristine (nonrandomized trial in n=9). During treatment, patient responses to chemotherapy were divided according to anatomic and clinical criteria: responders (n=5) versus nonresponders (n=4). Plasma chromogranin A rose progressively (P<0.0001) from control subjects (48.0+/-3.0 ng/mL) to benign pheochromocytoma (188+/-40.5 ng/mL) to malignant pheochromocytoma (2932+/-960 ng/mL). Parallel changes were seen for plasma norepinephrine (P<0.0001), though plasma epinephrine was actually lower in malignant than benign pheochromocytoma (P=0.0182). In bivariate analyses, chromogranin A, norepinephrine, and epinephrine discriminated between pheochromocytoma and control subjects (all P<0.0001), whereas in a multivariate analyses, norepinephrine was the best discriminator (P:=0.011). Chromogranin A was significantly different in benign versus malignant pheochromocytoma on both bivariate (P=0.0003) and multivariate (P:=0.011) analyses. After excision of benign pheochromocytoma, chromogranin A (P=0.028), norepinephrine (P=0.047), and epinephrine (P=0.037) all fell to values near normal. During chemotherapy of malignant pheochromocytoma (n=9), plasma chromogranin A (P=0.047) and norepinephrine (P=0.02) fell but not epinephrine. In 5 responders to chemotherapy, there were significant declines in chromogranin A (P=0.03) and norepinephrine (P=0.03) but not epinephrine; in 4 nonresponders, none of the transmitters changed. Plasma chromogranin A varied longitudinally with tumor response and relapse. We conclude that plasma chromogranin A is an effective tool in the diagnosis of pheochromocytoma, and markedly elevated chromogranin A may point to malignant pheochromocytoma. During chemotherapy of malignant pheochromocytoma, chromogranin A can be used to gauge tumor response and relapse.

Adolescent↗
PubMed1988

Urinary normetanephrine and metanephrine measured by radioimmunoassay for the diagnosis of pheochromocytoma: utility of 24-hour and random 1-hour urine determinations.

To validate the clinical usefulness of recently developed normetanephrine (NM) and metanephrine (M) RIA for the diagnosis of pheochromocytoma, urinary excretion of catecholamines and these metabolites were determined in 30 normal subjects, 40 patients with essential hypertension, 30 patients who were suspected to have but ultimately proven not to have a pheochromocytoma (pheochromocytoma-suspect), and 31 patients with a surgically verified pheochromocytoma. Abnormally high catecholamine excretion (epinephrine plus norepinephrine) was found in patients with pheochromocytoma compared with that in the normal subjects and the essential hypertension group. However, 3 of 31 patients with pheochromocytoma had urinary catecholamine excretion that overlapped the values in the pheochromocytoma-suspect group. Both urinary NM and M excretion also were elevated in patients with pheochromocytoma, but in 4 of 31 patients with pheochromocytoma urinary M excretion was within the range found in 1 or more of the other groups. Total M (NM plus M) excretion of more than 5485 nmol/day (as NM) was found in all patients with pheochromocytoma, and all patients had values that were higher than the highest values in the normal subjects or the patients with no evidence of pheochromocytoma. To save time and simplify the diagnostic work-up of patients suspected of having a pheochromocytoma, we also determined the NM and M concentrations in randomly voided 1-h urine samples in 24 patients with pheochromocytomas, 31 patients with essential hypertension, and 16 normal subjects. Abnormally high total M excretion was found in all patients with pheochromocytomas, and there was no overlap with the values in the patients with essential hypertension or the normal subjects. We conclude that total M measurements in both 24-h and random 1-h urine samples are useful in diagnosing pheochromocytomas.

Adolescent↗
PubMed2002

[Personal experience in diagnosis and localization of pheochromocytoma].

INTRODUCTION: Pheochromocytomas are most commonly tumours of adrenal medullary origin. Pheochromocytoma by definition produces and secretes catecholamines. Similar tumours that do not secrete active substances of any kind are called non functioning paragangliomas. The hallmark clinical manifestation of pheochromocytoma is hypertension accompanied with various signs and symptoms in excess of catecholamines or other bioactive substances. The early diagnosis of pheochromocytoma is important not only because it offers the possibility of curing hypertension but also because unrecognised pheochromocytoma is a potentially lethal condition. The aim of this article is to stress the specify of the clinical finding, diagnostical values of the laboratory tests and possibilities of morphological localizing techniques in a series of 98 patients with surgically proven pheochromocytoma. RESULTS: Over the period from 1954 to 2002 pheochromocytoma was diagnosed and surgically treated in 98 patients. The diagnosis was confirmed at operation except in patients who refused operation or continued the examination in other Clinical wards. There were 59 females and 48 males (F:M = 1.23:1), the age ranged from 7 to 64 years with the pick incidence in the second and third decades of life in males and the third and fourth decades of life in females. The basic clinical characteristic was hypertension which was found in 94% of patients with an approximately equal frequency of fixed and paroxysmal hypertension cases. The most often accompanning manifestations were headache (62%), perspiration (61%) and palpitations (65%). A high level of vanyl mandelic acid (VMA) and free catecholamines in 24-hour urine collection confirmed the diagnosis in 94% of cases. In boderline cases we performed dynamic tests, the most relevant among them being the test with phentolamin. It was positive in 95% of patients. Retropneumothomography contributed to a successful localisation of tumour in 83% of cases. Computed tomography (CT) was performed in 69 patients and was positive in 97% of them. Magnetic resonance imaging (MRI) localized the tumour in all 16 patient in whom it was performed. The whole body MIBG-J-131 (metaiodobenzylguanidine) scanes were positive in 92% (45/49) and false negative in the remainder of 8% (4/49) of cases. Selective angiography was performed in 40 patients and in all it was positive. DISCUSSION: Although pheochromocytomas were among the first recognized adrenal tumours, the prompt and safe diagnosis is mandatory up to date. The average annual incidence has been estimated by several epidemiologic studies to range from 0.8 to between 1.55 and 2.1 million persons per year. It is reported that it is curable cause of hypertension in 0.1% to 1% of cases. Pheochromocytoma has been classified as a "10% tumour" because various studies have shown that each of the characteristics mentioned bellow occurs with a frequency of approximately 10%: bilateral, extra-adrenal, multiple, malignant, familial and occurring in children. Our series of patients has a similar distribution: pheochromocytoma was in 9.2% of patients extra-adrenal, in 7.1% bilateral, in 9.2% multiple and in 4.08% malignant. Hypertension was the constant finding in 94% of our patients. Three clinical patterns of hypertenson have been observed. The first is paroxysmal hypertension, and the others are fixed or combinations of fixed and paroxysmal hypertension. According to our experience there were the equal incidence of all forms of hypertension. We noticed, like others, when the triad of headache, sweating and palpitations is accompanied by hypertension, the diagnosis of pheochromocytoma can be made with specify and sensitivity over 93%. In absence of this finding the diagnosis can be excluded with certainty of 99%. As a specify of the clinical finding, we mention two patients with manifestations of hypercorticism, two patients with pheochromocytoma of the urinary bladder, and four with MEN syndrome (one with MEN 2A and three with MEN 2B). For confirming the diagnosis the most relevant laboratory test was the higher level of VMA and free catecholamines in 24-hour urine collections. Once pheochromocytoma has been diagnosed by biochemical analyses, the anatomic location of the tumour or tumors must be determined. Currently, the best approach is to obtain MIBG-J-131 scan and then to perform MRI or CT of the abdomen and other areas identified on MIBG scan in order to provide more accurate spatial information. With this approach the great majority of pheochromocytomas can be localized. CONCLUSION: There is no classic picture, no stereotype for pheochromocytoma, although the history and physical finding are helpful. Patients come to the clinician in a variety of ways and settings. They may have classic attacks of hypertension accompanied with headache, perspiration and paplpitations or they may have identical symptoms and physical findings as the patients with primary hypertension. On the other hand, they may have signs and symptoms of diabetes mellitus, hyperthyroidism, hypercalcaemia, congestive heart failure, myocardial infarction, malignant hypertension or a variety of other conditions. Rarely, they have no complaints at all. Once the diagnosis was made, spatial localizing of the tumour or tumours, and surgical treatment are necessary. Unrecognized disease may be fatal.

Adolescent↗
PubMed1991

A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience.

Pheochromocytoma is an unusual but potentially devastating tumor. Although a high index of suspicion is necessary, the likelihood of a pheochromocytoma is lower in the absence of the typical symptoms and findings. Nonetheless, screening must be broadened to include patients with a lower risk of the disease, such as those with resistant or labile hypertension who are minimally symptomatic. Extensive diagnostic evaluations should be reserved for those whose clinical or laboratory findings are more suggestive. Symptoms in a group of patients in whom a pheochromocytoma was seriously considered but excluded overlap symptoms in patients with a pheochromocytoma. Certain symptoms are useful: flushing to suggest a non-pheochromocytoma illness; visual symptoms, flank pain, and pallor to suggest that a pheochromocytoma is more likely. Combinations of symptoms can be of value: 2 or more symptoms from the triad of headache, palpitations, and diaphoresis were present in the majority of pheochromocytoma patients, but in a smaller number of non-pheochromocytoma patients. The presence of the entire triad is more specific, but less sensitive. New hypertension, or hypertension associated with unexplained orthostatic hypotension, are suggestive of an underlying pheochromocytoma. Twenty-four-hour urine studies are consistently abnormal in patients with a pheochromocytoma, but are also elevated in a significant proportion of non-pheochromocytoma patients. Values greater then 1.5-2-fold above the upper limit of normal are very suggestive that a pheochromocytoma is present, and warrant a more intensive subsequent evaluation. Imaging studies are reliable in the diagnosis of pheochromocytoma, and can help to confirm or exclude the disease. Patients with a higher clinical likelihood and any elevated urinary testing, or with a lower clinical likelihood and persistently and/or significantly elevated urinary testing, should have imaging studies performed. This combination of clinical screening, 24-hour urinary testing, and imaging studies is a useful and reliable approach to patients suspected of harboring a pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1991

Chromogranin A storage and secretion: sensitivity and specificity for the diagnosis of pheochromocytoma.

Chromogranin A, co-stored and co-released with catecholamines from adrenal medullary and sympathetic neuronal vesicles, is elevated in the plasma of patients with pheochromocytoma. The usefulness of the hormone in the differential diagnosis of hypertension is examined. An elevated level of chromogranin A had comparable diagnostic sensitivity (83%, 24/29) to, but greater diagnostic specificity (96%, 86/90) than the level of plasma catecholamines when subjects with pheochromocytoma (n = 29) were evaluated in comparison to several reference groups, including normotensive controls (n = 49), subjects with essential hypertension (n = 28), subjects with renovascular hypertension (n = 5), and subjects with primary aldosteronism (n = 3). Subjects with signs or symptoms suggesting pheochromocytoma, but in whom the diagnosis was ultimately ruled out (n = 5) had normal plasma levels of chromogranin A. A modest rise in chromogranin A in those with essential hypertension, and correlation of chromogranin A with diastolic blood pressure in normotensive patients and patients with essential hypertension did not impair the diagnostic usefulness of chromogranin A for pheochromocytoma. Renal failure was associated with an elevated plasma chromogranin A independently of blood pressure. Plasma chromogranin A correlated with tumor mass, tumor chromogranin A content, tumor norepinephrine content, and urinary vanillylmandelic acid excretion; it did not correlate with plasma or urinary catecholamines, nor with blood pressure in patients with pheochromocytoma. Plasma chromogranin A levels did not differ in subjects with pheochromocytoma when stratified by age, sex, tumor location, or tumor pathology. Several drugs used in the diagnosis or treatment of pheochromocytoma (clonidine, metoprolol, phentolamine, and tyramine) had little effect on plasma chromogranin A concentration. Within the pheochromocytoma, chromogranin A was localized along with catecholamines to the soluble core of chromaffin granules, where it accounted for 18 +/- 5% of vesicle soluble protein. We conclude that 1) chromogranin A emerges along with catecholamines from pheochromocytoma chromaffin granules; 2) plasma chromogranin A is a sensitive and specific diagnostic tool in evaluation of actual or suspected pheochromocytoma; 3) plasma chromogranin A predicts pheochromocytoma tumor size and overall catecholamine production; and 4) drugs commonly employed in the diagnosis or treatment of pheochromocytoma have little effect on plasma chromogranin A level, preserving the usefulness of chromogranin A in evaluating pheochromocytoma. Thus, measurement of chromogranin A provides a useful adjunct to the diagnosis of pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2003

Pheochromocytoma: the expanding genetic differential diagnosis.

Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.

Adrenal Gland Neoplasms↗
PubMed2002

[Surgical treatment of pheochromocytoma--personal experience].

UNLABELLED: The first description of the adrenal gland dates since 1563 by Eustachius in a study "Opscula anatomica". Despite earlier recognition of the presence of adrenals and division into cortex and medulla, the precise observations of Addison appeared in 1855 that the essential role of these glands was recognized in patients who died with adrenal destruction secondary to tuberculosis. Frankel first described a medulary adrenal tumour in 1886. In 1912 the pathologist Pick formulated the descriptive term pheochromocytoma. The first surgical removal of pheochromocytoma in Europe was performed by Rouks in 1926 and by Mayo in USA in 1927. The work of the later had greater impact. For a long period of time the Military Medical Academy is involved in clinical diagnosis and management of adrenal tumours. The first description of diagnosed pheochromocytoma was by Professor Ratibor Mitshitsh. The first surgical removal of pheochromocytoma in the Military Medical academy and in Yugoslavia was performed by Professor Isidor Papo. Over the period January 1974-December 2001, 268 patients with tumours of adrenal origin(93 patients/34.7%/had pheochromocytoma) underwent surgical treatment in the Military Medical Academy. Of our particular interest was the relation between the surgical approach to pheochromocytoma and the incidence and severe intraoperative and immediate postoperative complications. Although numerous studies favorise transabdominal and thoracic approach, our experience in flank approach is very favorable. By the lateral high intercostal approach above the eleventh costae we operated on 67 (72%) patients with only one (1.5%) major complication--cardiac arrest. With successful reanimation the patient survived. The transperitoneal approach was performed in 21 (22%) cases and we had 7 (33.1%) severe complications: one lethal outcome, cardiac arrest, injury of the aorta, injury of the VCI, postoperative bleeding that required relaparatomy and two splenectomies. The lethal outcome was the result of nonidentified ectopic retropancreatic pheochromocytoma that was not identified preoperatively and intraoperatively. At that time ultrasound, CT and MRI were not available. By transthoracic and posterior approach we operated on a small number of pheochromocytomas. DISSCUSSION: We analysed the advantages and disadvantages of some surgical approaches and our experience in these methods of management of pheochromocytoma and other adrenal tumours; we confirmed multiple advantages of flank intercostal approach above the eleventh costae compared to other approaches. This approach is simple, extrapleural and extraperitoneal. It offers a broad surgical field with the adrenal in its centre which permits an atraumatic operation with little risk of complications. CONCLUSIONS: The flank intercostal approach above the eleventh costae is indicated(option of choice) in unilateral pheochromocytoma and other unilateral adrenal tumours. The transabdominal approach is indicated in cases of bilateral pheochromocytomas, in cases of abdominal localization of ectopic pheochromocytomas, in tumours which involve the VCl and most of the left renal vein, and in patients with extremely large adrenal tumours. The thoracic approach is indicated in intrathoracic ectopic pheochromocytomas.

Adrenal Gland Neoplasms↗
PubMed1988

Pheochromocytoma.

Although pheochromocytoma is an uncommon cause of secondary hypertension, it is also a curable form of hypertension. With proper treatment, the outlook for patients with pheochromocytoma is excellent. If undiagnosed or untreated, pheochromocytoma causes serious complications and death. The key to reaching the diagnosis is a high index of suspicion coupled with careful clinical evaluation and laboratory testing. Our ability to diagnose and localize pheochromocytoma has improved vastly, owing largely to the modern biochemical and radiologic techniques. Despite this, a number of pheochromocytomas remain undiagnosed only to be uncovered after a serious complication or at postmortem. The diverse manifestations and problems presented by patients with pheochromocytoma can be managed only with combined medical and surgical expertise, with assistance from our colleagues from the radiology and anesthesiology disciplines. Although sporadic pheochromocytoma is the most common form of presentation, the overall clinical picture may depend on the subset of affected individual--childhood, pregnancy, associated MEN, and neurocutaneous syndromes. Fortunately, more than 90 per cent of all pheochromocytomas originate in the adrenal gland, but the tumor can occur at any site in the sympathetic chain. The spectrum of clinical manifestations is so wide that a pheochromocytoma may mimic a variety of common disorders. It is as challenging to diagnose what is not a pheochromocytoma as it is to confirm its diagnosis. Surgical removal of pheochromocytoma is the treatment of choice. With proper preoperative medical management aimed at blocking the effects of catecholamines, operative mortality should be close to zero. For patients with inoperable, malignant, recurrent, or multicentric pheochromocytomas, chronic medical therapy is indicated in the form of alpha- and/or beta-blockade or inhibition of catecholamine synthesis with alpha-methyl-para-tyrosine. An understanding of the pathophysiology and natural course is vital to the rational management of patients with pheochromocytoma.

Humans↗
PubMed2002

Differential heparanase-1 expression in malignant and benign pheochromocytomas.

INTRODUCTION: Extracellular matrix (ECM) degradation is an essential step that allows tumor cells to penetrate a tissue barrier and become metastatic. Heparanase-1 (HPR) is an endoglycosidase that specifically degrades heparan sulfate proteoglycans, a chief component of the ECM. Previous studies have demonstrated HPR expression in various malignancies and that there is differential HPR expression between benign and malignant tumors. Currently, there is no technique that can reliably predict the malignant behavior of some pheochromocytomas. This study tests whether HPR is differentially expressed in malignant and benign pheochromocytomas. METHODS: Paraffin-embedded specimens from 29 pheochromocytomas were evaluated. The tissues were collected from surgical specimens over a 10-year period from 26 patients (8 males, 18 females) with a mean age of 47 years (range 19-78 years, median 47 years). One female patient underwent 3 separate operations for malignant pheochromocytoma and thus provided 3 specimens. Another female patient had both the primary tumor and a liver metastasis processed, and therefore provided 2 specimens. Patient charts and pathology reports were reviewed to classify the pheochromocytomas as either benign or malignant. Based on clinical behavior and/or pathological evidence of metastasis or invasion into surrounding tissues, 10 specimens were malignant and 19 had benign behavior. As a control, normal adrenal tissue from 3 nephrectomy specimens was included in the study, as was tissue from 1 adrenocortical adenoma. All 33 specimens were tested for HPR gene expression by in situ hybridization (ISH) with an antisense RNA probe and immunohistochemistry (IHC) with an anti-HPR antibody. Statistical analysis was done using the chi(2) test of proportions to determine if HPR expression correlated with malignancy using ISH, IHC, or both tests together. RESULTS: Using ISH, the percentage of HPR expression in the malignant pheochromocytomas was 50% while HPR expression in the benign tumors was 21% (P = 0.11). Using IHC, the percentage of HPR expression in the malignant pheochromocytomas was 80% while HPR expression in the benign tumors was 32% (P = 0.01). Considering both tests cumulatively, all 10 malignant pheochromocytomas stained positive for HPR by ISH and IHC, while only 37% of the benign tumors were positive for HPR expression (P = 0.001). The one adrenal adenoma and the 3 normal adrenal glands processed stained negative for HPR expression by both ISH and IHC. CONCLUSIONS: HPR expression is higher in malignant pheochromocytomas than in benign pheochromocytomas or normal tissue. HPR may contribute to the invasive characteristics of malignant pheochromocytomas and might be used as a marker to distinguish malignant from benign pheochromocytomas. HPR expression might also be used as a prognostic tool in guiding long-term patient follow-up.

Adrenal Gland Neoplasms↗
PubMed2001

Plasma adrenomedullin concentrations in patients with adrenal pheochromocytoma.

BACKGROUND: The hypotensive peptide adrenomedullin was first isolated in extracts of human pheochromocytoma. There is, however, no information available on the behaviour of circulating adrenomedullin or on the correlation with catecholamines in patients with pheochromocytoma. OBJECTIVES: 1) to investigate whether plasma adrenomedullin levels were changed in 10 patients with pheochromocytoma when compared to 21 healthy subjects and 16 patients with essential hypertension; 2) to determine whether or not adrenomedullin has a counter-regulatory role in catecholamine excess in pheochromocytoma or is responsible for hemodynamic modifications before and after tumour resection; 3) to determine tissue distribution of iradrenomedullin in the pheochromocytoma. METHODS: Plasma adrenomedullin and catecholamine levels were measured in all patients with pheochromocytoma before and four weeks after tumour removal. In the four patients undergoing resection of tumours, plasma levels of adrenomedullin were measured at different time-points during surgery. RESULTS: The mean plasma adrenomedullin concentrations ( SD) in patients with pheochromocytoma (37.9 +/- 6pg/ml) were significantly higher (p<0.0001) than those in normal subjects (13.7 +/- 6.1 pg/mI) and patients with essential hypertension (22.5 +/- 9.lpg/ml). Adrenomedullin levels correlated with plasma noradrenaline (r = 0.516, p = 0.0124). In all patients with pheochromocytoma, plasma adrenomedullin concentrations decreased after removal of tumours (from 37.9 +/- 6 to 10.9 +/- 4.6 pg/ml; p < 0.0001). In the four patients studied during surgery, baseline plasma adrenomedullin and noradrenaline levels were markedly elevated, and increased significantly with tumour manipulation, decreasing 24 hours after operation. Adrenal medulla cells surrounding the pheochromocytoma site stained for ir-adrenomedullin, whereas only isolated cells of pheochromocytoma stained for the peptide. CONCLUSIONS: This study demonstrates that circulating adrenomedullin is increased in pheochromocytoma, and is also correlated with plasma noradrenaline levels. Adrenomedullin may represent an additional biochemical parameter for clinical monitoring of patients with pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1993

Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease.

BACKGROUND: Pheochromocytoma is a feature of two disorders with an autosomal dominant pattern of inheritance--multiple endocrine neoplasia type 2 (MEN-2) (with medullary thyroid carcinoma and hyperparathyroidism) and von Hippel-Lindau disease (with angioma of the retina, hemangioblastoma of the central nervous system, renal-cell carcinoma, pancreatic cysts, and epididymal cystadenoma). The frequency of these syndromes in patients with pheochromocytoma is not known. METHODS: In an unselected group of patients with pheochromocytoma, we performed pentagastrin tests, parathyroid hormone assays, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain, ophthalmoscopy, CT imaging of the abdomen, and ultrasonography of the testes. We also screened members of families with MEN-2 or von Hippel-Lindau disease for pheochromocytoma by measuring plasma and urine catecholamines and plasma chromogranin A and by performing abdominal ultrasonography, CT and MRI, and metaiodobenzylguanidine scintigraphy. RESULTS: Nineteen of 82 unselected patients with pheochromocytomas (23 percent) were carriers of familial disorders; 19 percent had von Hippel-Lindau disease and 4 percent had MEN-2. Prospectively, in 36 of 79 subjects at risk for pheochromocytoma (46 percent), 42 unsuspected pheochromocytomas were found. Overall, there were 130 patients with 185 pheochromocytomas; 43 had von Hippel-Lindau disease, 24 had MEN-2, and 63 had sporadic tumors. The patients with familial and those with sporadic pheochromocytomas differed in mean age at diagnosis (32 vs. 46 years, P < 0.001), multifocal localization (55 vs. 8 percent, P < 0.001), and cancer (0 vs. 11 percent, P = 0.005); but not in the frequency of extraadrenal tumors (24 vs. 16 percent). Thirty-eight percent of carriers of von Hippel-Lindau disease and 24 percent of carriers of MEN-2 had pheochromocytoma as the only manifestation of their syndrome. CONCLUSIONS: All patients with pheochromocytomas should be screened for MEN-2 and von Hippel-Lindau disease to avert further morbidity and mortality in the patients and their families. All patients in families with MEN-2 or von Hippel-Lindau disease should be screened for pheochromocytoma, even if they are asymptomatic.

Adolescent↗
PubMed1999

Altered sympathetic and vagal modulations of the cardiovascular system in patients with pheochromocytoma: their relations to orthostatic hypotension.

To examine sympathetic and vagal cardiovascular regulatory mechanisms in the pathogenesis of orthostatic hypotension in pheochromocytoma, we continuously monitored blood pressure (Finapres) and RR interval (electrocardiogram) in supine and standing positions in 12 patients with pheochromocytoma, 43 patients with essential hypertension, and 30 normotensive subjects. Mayer wave power spectrum of systolic blood pressure variability (approximately 0.1 Hz) and respiratory power spectrum of the RR interval variability (approximately 0.25 Hz) were taken as measures of sympathetic vascular and cardiac vagal modulations, respectively. Systolic blood pressure decreased more upon standing in pheochromocytoma patients (-21 +/- 7 mm Hg) than in normotensive subjects (-5 +/- 2 mm Hg) or essential hypertensive patients (-3 +/- 2 mm Hg) (P < .005 for both), whereas heart rate tended to increase most in the pheochromocytoma group. Postural reduction in systolic blood pressure was highly correlated with postural increase in heart rate (reciprocal change in RR interval) in the pheochromocytoma group (r = 0.716, P < .01) suggesting that baroreflex is well functioning in those patients. The Mayer wave power spectrum in recumbency was extremely depressed in pheochromocytoma patients (1.1 +/- 0.2 mm Hg2) compared with normotensives (4.5 +/- 0.8 mm Hg2) or essential hypertensives (5.6 +/- 0.6 mm Hg2) (P < .001 for both). This parameter increased significantly with standing in all groups but remained lower in patients with pheochromocytoma (5.1 +/- 1.0 mm Hg2) than in normotensives (7.1 +/- 0.9 mm Hg2, P = NS), whereas essential hypertensive patients demonstrated far greater value (19.2 +/- 3.8, P < .01 for both). The respiratory power spectrum of the RR interval in recumbency of pheochromocytoma patients (189 +/- 54 msec2) was less than in normotensive subjects (714 +/- 100 msec2, P < .001) but did not differ from that in patients with essential hypertension (214 +/- 41 msec2). The respiratory power spectrum of the RR interval upon standing was markedly suppressed in pheochromocytoma patients (36.9 +/- 16.7 msec2) compared with normotensive subjects (129.5 +/- 23.6 msec2) or essential hypertensive patients (126.6 +/- 28.6 msec2) (P < .001 for both). Postural decrement in the respiratory power spectrum of the RR interval correlated positively with postural increase in heart rate (r = 0.577, P < .05) in patients with pheochromocytoma. After successful surgery (n = 9), the Mayer wave power spectrum of the systolic blood pressure and the blood pressure response to orthostasis were normalized. These data suggest that altered sympathetic vascular regulation is central to the pathogenesis of orthostatic hypotension in pheochromocytoma, whereas cardiac vagal regulation acts to compensate.

Adrenal Gland Neoplasms↗
PubMed1990

Captopril improves hypertension and cardiomyopathy in rats with pheochromocytoma.

Hypertension and cardiomyopathy are prominent findings in humans and rats harboring pheochromocytomas, tumors that can secrete enormous quantities of catecholamines. We have previously found that alpha- and beta-adrenergic receptor antagonists may ameliorate the hypertension and cardiomyopathy found in New England Deaconess Hospital rats implanted with pheochromocytoma. The present studies were designed to determine the possible action of the angiotensin converting enzyme inhibitor captopril on these changes in rats harboring pheochromocytomas. Rats were implanted with transplantable pheochromocytomas and treated with captopril dissolved in the drinking water (1 mg/ml) for 4-6 weeks. Systolic blood pressure was monitored by using the tail-cuff technique. In the rats with pheochromocytoma, blood pressure progressively increased to 184 +/- 3 mm Hg after the tumor was implanted. However, in rats with pheochromocytoma treated with captopril in the drinking water before the development of hypertension, blood pressure did not increase (137 +/- 3 mm Hg). In rats with pheochromocytoma with established hypertension, captopril normalized the systolic blood pressure. Plasma norepinephrine was markedly elevated to a similar extent in both groups compared with unimplanted control rats. Plasma renin activities were slightly lower in rats with pheochromocytoma compared with unimplanted control rats. Treatment with captopril of rats with pheochromocytoma did not modify contraction of isolated rings of thoracic aorta exposed in vitro to either phenylephrine or angiotensin II. Treatment with captopril markedly attenuated the cardiomyopathy induced by pheochromocytoma. These results demonstrate that captopril prevents the development of hypertension despite markedly elevated concentrations of catecholamines. In addition, captopril attenuates catecholamine-induced cardiomyopathy in pheochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Gland Neoplasms↗
PubMed2006

Review: Should patients with apparently sporadic pheochromocytomas or paragangliomas be screened for hereditary syndromes?

CONTEXT: The recent identification of germline mutations of the mitochondrial complex II genes in variants of paraganglioma/pheochromocytoma syndrome has enlarged the number of known causative genes for hereditary pheochromocytoma. A question confronting clinicians is whether they should screen patients with apparently sporadic pheochromocytomas for unsuspected germline mutations of some or all of the seven genes known to cause hereditary paraganglioma or pheochromocytoma (NF1, VHL, RET, MEN1, SDHD, SDHC, and SDHB). A positive answer was suggested by a report that placed the estimate of hereditary disease in apparently sporadic pheochromocytoma as high as 24%. EVIDENCE ACQUISITION: We applied clinically useful criteria to a review of the literature, defining cases of apparently sporadic pheochromocytoma as those without a suspicious personal or family history, with a focal, unilateral pheochromocytoma, and presenting at age less than 50 yr. EVIDENCE SYNTHESIS: We reduced the overall estimate of unsuspected hereditary pheochromocytoma patients with apparently sporadic pheochromocytoma to approximately 17%. Mutations in only three genes (VHL, SDHB, and SDHD) accounted for almost this entire minority, and unsuspected RET mutation was rare. Costs, coverage by insurance, the potential effect on insurability, and deficient information for populations outside of referral centers should be considered before recommending genetic testing in patients with apparently sporadic presentations of pheochromocytomas. CONCLUSION: We recommend genetic testing for patients with an apparently sporadic pheochromocytoma under the age of 20 yr with family history or features suggestive of hereditary pheochromocytoma or for patients with sympathetic paragangliomas. For individuals who do not meet these criteria, genetic testing is optional.

Adult↗
PubMed2002

[Results of surgical treatment of pheochromocytoma at the Institute of Endocrinology of the Clinical Center of Serbia in Belgrade].

Pheochromocytoma is a rare tumour that synthesis extensive amounts of cathecholamines. It is usually called a "ten percent" tumour, as it is inherited in nearly 10% of cases, extra-adrenal in 10%, bilateral, multicentric and malignant in also nearly 10% of cases. Nowadays, surgery of pheochromocytoma is very successful as a result of well equipped laboratory techniques, radiological diagnosis and pharmacological drugs in preoperative therapy and control examinations during surgery. Although the operative technique and anaesthesia are delicate, operative risk is reduced to minimum, and definite recovery can be achieved in almost all benign diagnosed pheochromocytomas. Unrecognized pheochromocytomas remain the main problem, often ending with sudden death because of cerebrovascular complications or myocardial infarction, and are diagnosed during autopsy. The aim of the study is to underline the principal characteristics of pheochromocytomas and evaluate the facts that influence the diagnosis and outcome of the treatment. Medical records of the patients operated on for pheochromocytoma in our Institution are analysed. From 1981 to 2001, 102 patients underwent surgery for pheochromocytoma, 71 females and 31 males, average age 42 years (range 9 to 71). Laboratory confirmation was based on 24-hour urine cathecholamines, and in 12 patients only plasma cathecholamines were determined. In imaging studies, we used ultrasound (US), computerised tomography (CT) and nuclear magnetic resonance (NMR). If there was a suspicion of inherited or extra adrenal form of a tumour, we also used Metaiodbenzilguanidine scan marked with radioactive I131 (I131-MIBG). Diagnostic confirmation of tumours localisation was completely reliable. In 89 patients adrenal pheochromocytoma was found (12 bilateral, 2 with paraganglioma). In 13 patients, pheochromocytoma was extra-adrenal. Inheritated character was registered in 18 patients (MEN2 in 16, NF-1 in 2). Malignant pheohromocytoma was found in 11 patients, in 4 of 13 with extra-adrenal tumours, and in 7 of 89 with adrenal tumours. We prepared all patients with diagnosed pheochromocytoma for operation with phenoxybenzamine in daily doses of 20 to 90 mg, no matter whether they were normotensive or with hypertension. Two days before operation, we included propranolol in the therapy in doses of 20 mg twice or three times a day. Surgery was done in neuroleptic anaesthesia. We performed 100 primary operations and 9 reoperations (in 2 patients, the first operation was carried out in another institution), and extracted 123 tumours. In 2 patients, during reoperation we extracted the opposite adrenal tumour, in one recurrent benign tumour, and in the others, reoperation was done because of recurrent malignant pheochromocytoma. Hypertension was completely corrected in 79% of operated patients, reduced in 13%, and in 7% there was no effect on hypertension We observed the following operative complications: peritonitis due to a small bowel lesion (1), infection and wound dehiscence (1), pleural effusion (1), pneumothorax (1), gastrointestinal haemorrhage (1), haemathoma (1), temporary hemiparesis (1) and seroma of the wound (1). There was no operative mortality.

Adolescent↗
PubMed2002

[Pheochromocytomas as adrenal gland incidentalomas].

Adrenal incidentalomas are a heterogeneous group of pathological entities, including benign or malignant adrenocortical or medullary tumors, hormonally active or inactive lesions, which are identified incidentally during the examination of nonadrenal-related abdominal complaints. About 1.5% to 23% of adrenal incidentalomas are pheochromocytomas. Composite pheochromocytoma is a rare tumour of adrenal medulla with divergente clinical course. This type of pheochromocytoma is designated "composite" or "mixed," depending on whether pheochromocytoma and nonpheochromocytoma components show the same embryologic origin. Nonpheochromocytoma components found in the composite pheochromocytoma include ganglioneuroma, ganglioneuroblastoma, neuroblastoma, and malignant schwannoma. The biologic behavior of composite pheochromocytomas may be as difficult to predict as more traditional pheochromocytomas; based on the number of cases reported to date the presence of areas resembling ganglioneuroblastoma or neuroblastoma does not necessary indicate a poor prognosis. Some may behave in a malignant fashion with metastasis by a component of the tumour which has neural features. Pheochromocytomas and paragangliomas are well-defined entities. Some of their nonsporadic associations and unusual morphological appearances are not universally appreciated. We report on a rare association of left adrenal CP, with typical right adrenal phochromocytoma and retroperitoneal paraganglioma, and a review of literature. We analyzed the clinical and immunohistochemical features in a 24-year-old woman with composite pheochromocytoma localized in the left adrenal gland and associated with blood pressure of 200/140 mmHg. Abdominal computed tomography and 131-J MIBG revealed a 65 x 60 mm mass in the right adrenal gland, but no revealed 45 x 40 mm retroperitoneal mass and 20 x 20 mm mass in the left adrenal region. Serum and urinary adrenaline levels were high, and catecholamine levels in the blood sample of the selective adrenal vein, were also high. Bilateral adrenalectomy and retroperitoneal mass were surgically removed without complications. Clinical symptoms were absent 6 years after surgery. After surgery the patient gave birth to two healthy babies. Immunohistochemical analyses revealed that tumour cells of right adrenal pheochromocytoma and retroperitoneal paraganglioma were strongly positive for neurone specific enolase, synaptophisin and chromogranin A. The left adrenal tumour showed pheochromocytoma, ganglioneuroma and neuroblastoma components. Immunoreactivity of this tumour added several features to the wide immunohistochemical spectrum. This case demonstrates the indolent behavior of sporadic-type CP and retroperitoneal paraganglioma in an adult patient. Unusual morphological features of CP occur in a substantial number of cases and may cause diagnostic problems.

Adrenal Gland Neoplasms↗
PubMed1994

The predictive value of diagnostic tests for pheochromocytoma.

BACKGROUND: Ascertaining or excluding a pheochromocytoma may be difficult. The purpose of this study is to identify preoperative tests that are good predictors of a pheochromocytoma. METHODS: Patients presumptively diagnosed with a pheochromocytoma based on clinical assessment, plasma or urinary catecholamines, computed tomography, or magnetic resonance imaging were analyzed. The sensitivity, specificity, positive, and negative predictive values were determined for each test based on the pathologic finding of a pheochromocytoma. Data were analyzed with Student's t test or Fisher's exact test. RESULTS: Of 14 patients, seven had pathologically proven pheochromocytomas, whereas three had cortical adenomas. In four patients, a pheochromocytoma was excluded by repeat testing. The 24-hour urinary mean metanephrine levels were significantly different between patients with and without pheochromocytomas (5.8 micrograms vs 0.5 micrograms, p = 0.05) and had the best positive predictive value (83%) and negative predictive value (100%) of the biochemical tests. T2-weighted magnetic resonance imaging had a 100% positive and negative predictive value. Age, sex, symptoms, blood pressure, tumor location, tumor size, and plasma catecholamine levels could not accurately predict or exclude a pheochromocytoma. CONCLUSIONS: T2-weighted magnetic resonance imaging is the imaging study of choice for predicting a pheochromocytoma. The 24-hour urinary metanephrine level is the single best biochemical indicator of a pheochromocytoma. Plasma catecholamine levels and computed tomography are not helpful in diagnosing or excluding a pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed1987

Usefulness of basal catecholamine plasma levels and clonidine suppression test in the diagnosis of pheochromocytoma.

In the present paper we report our experience on the utility of basal plasma catecholamine (CA) measurement and of the clonidine-suppression test in the diagnosis of pheochromocytoma. Basal noradrenaline (NA) and adrenaline (A) were assayed in plasma samples of 27 subjects affected by pheochromocytoma. When compared to basal values obtained in hypertensive patients without pheochromocytoma, one or both the CA resulted pathologically elevated in all patients except one. The response to the clonidine-suppression test was evaluated in 41 hypertensive patients suspected of having a pheochromocytoma measuring plasma NA and A in basal conditions and 2 and 3 h after oral administration of 300 micrograms clonidine. Extensive laboratory and instrumental findings confirmed the presence of pheochromocytoma only in 12 patients. Among the other 29 patients basal plasma CA resulted higher than normal in 4 patients. In patients without pheochromocytoma clonidine induced a significant fall in both NA and A plasma levels. The decrease in NA was observed in each patient. The 12 patients with pheochromocytoma showed a pathological elevation of one or both the CA. In this group clonidine did not significantly suppress plasma CA. The individual responses were extremely variable. Our data confirm the validity of plasma CA measurement as a diagnostic tool for the diagnosis of pheochromocytoma. The results of the clonidine-suppression test were generally confirmatory of the basal CA plasma values but in the 4 hypertensive patients without pheochromocytoma who showed basal plasma CA higher than normal clonidine resulted a useful tool in excluding the presence of pheochromocytoma.

Adolescent↗