Pheochromocytoma in Italy: a multicentric retrospective study

OBJECTIVE: To conduct an epidemiological study on pheochromocytoma in Italy. METHODS: Data on 284 patients with pheochromocytoma observed between 1978 and 1997 were collected from 18 Italian centers through a questionnaire reporting epidemiological, clinical, laboratory, radiological and surgical data. RESULTS: 53.6% of the patients were females and 46.4% were males. Thirty-two tumors were discovered as incidental adrenal masses. The most frequent referred symptoms were palpitations (58.1%), headache (51.9%), sweating (48. 8%) and anxiety (35.3%). Their association was present only in 15.5% of patients. Paroxysmal symptoms were reported in 67.1% and hypertensive crises in 59.7% of patients. Normal blood pressure (systolic and diastolic) was present both in the supine and upright positions in 21.1% of patients. Among laboratory assays, urinary vanylmandelic acid (VMA) was the most widely used (58.1%) and was the least sensitive (25% of false negative results). Basal plasma catecholamines were found to be normal in 11.3% of patients but were always elevated when sampled during a hypertensive paroxysm. A clonidine suppression test was performed in 38 patients with no adverse side effects. It gave a false negative response in 2 patients. A glucagon test was performed in 21 patients. It was interrupted for acute hypertension in 52.4% of patients. Only 5/21 patients were normotensive and had normal basal plasma catecholamines. In these patients the test gave a positive response in four (80%). CT (79.6%) and I-MIBG scintigraphy (68.5%) were the most widely used methods for tumor localization. CT sensitivity was 98.9% for intra-adrenal and 90.9% for extra-adrenal tumors. MIBG sensitivity was 88.5%. In the 263 patients who underwent surgery, the tumor was intra-adrenal in 89.4%, extra-adrenal in 8.5%, intra- and extra-adrenal in 2.1%, and bilateral in 11.0% of patients. Malignancy was reported in 9.9% of cases. Surgery caused remission of hypertension in 59.3%, improvement in 26.8%, and no changes in 13. 9% of patients. In the last group the interval between initial symptoms and diagnosis was significantly longer. CONCLUSIONS: The present study confirms that the clinical presentation of pheochromocytoma is variable and aspecific. Normotension is often present and often the tumor is discovered incidentally. An indication for the routine use of screening methods more sensitive than urinary VMA is strongly suggested. The clonidine test was found to be safe and should be preferred to the glucagon test which has to be restricted to very selected patients. CT and MIBG scintigraphy are almost always successful in localizing the tumor. Reversal of hypertension by surgery seems to depend on an early diagnosis.     

Pheochromocytoma associated ventricular tachycardia blocked with atenolol

Ventricular tachycardia in patients with phenochromocytoma is rare. We report a patient with a norepinephrine-secreting extra-adrenal pheochromocytoma who had exercise induced ventricular tachycardia. Prior to diagnosis, the patient was treated with a selective beta 1 blocker, atenolol, which resulted in suppression of the dysrhythmia and amelioration of the hypertension. This is the first reported case of selective beta blockade suppressing ventricular tachycardia in a patient with a pheochromocytoma. Electrocardiographic abnormalities described in patients with pheochromocytoma are reviewed.     

嗜铬细胞瘤的诊断及其发病机制研究

嗜铬细胞瘤是来源于肾上腺髓质和肾上腺外嗜铬组织的分泌儿茶酚胺的肿瘤,是内分泌性高血压的重要原因,可导致心、脑、肾血管系统的严重并发症。其在高血压人群中的患病率约为1.9%,早期发现及正确诊断、治疗嗜铬细胞瘤患者具有重要的意义。应高度重视嗜铬细胞瘤发病机制及治疗的研究。     

The importance of radiology in the localization of pheochromocytoma

The usefulness of different radiologic studies in localizing the tumor was evaluated in 26 patients with a firmly established diagnosis of pheochromocytoma. The site of the lesion was correctly identified in 8% of the cases by the plain abdominal x-ray films: in 11% by the plain thoracic films; in 34% by uronephrotomography; in 88% by angiography and in 6 patients (100%) in whom computed tomography scans (CT) were performed. The tumors were intra-adrenal in 19 patients and extra-adrenal in the remaining 7 cases. Of the latter, two were found in the organ of Zuckerkandl, two were abdominal para-aortic, two others in the para-aortic region of thorax, and one with intra an extra-adrenal tumors. It is concluded that CT scans are quite successful in preoperative localization of pheochromocytoma. The non-invasive nature of the technique makes it the method of choice in the anatomical localization of this type of tumors.     

Extra-adrenal pheochromocytoma (paraganglioma).

The authors describe the case of a 19-year-old female patient with an abdominal paraaortic extra-adrenal pheochromocytoma (paraganglioma), presenting arterial hypertension. The predominant catecholamine produced by the tumor was norepinephrine (4110 pg/ml; normal < 450 pg/ml). 131I metaiodobenzylguanidine (131I-MIBG), computed tomography and magnetic resonance imaging allowed location and characterization of the tumor. Histologically the tumor (weight = 34.2 g; 5.8 x 4 x 3 cm) was a typical pheochromocytoma.     

Comparison of MIBG scintigraphy and computerized tomography in the localization of pheochromocytomas

Ninety-nine patients suspected of having pheochromocytoma were studied with MIBG scintigraphy and in 92 of them were studied with computed tomography. In 49 patients, the diagnosis was ruled out, in 3 patients it remained doubtful, and in 47 patients it was confirmed. Two patients had epinephrine--and/or norepinephrine--non-secreting tumors and 45 had secreting pheochromocytomas. In these latter patients, there were 4 scintigraphic false-negatives, all intra-adrenal, and 4 computed tomography false-negatives, 3 extra-adrenal and 1 intra-adrenal. For about 80% of the patients and/or the tumor sites, both methods were thus in agreement. They were complementary in the remaining 20%. The advantage of scintigraphy is to screen the whole body with high specificity and to locate extra-adrenal sites or metastases of pheochromocytoma with better accuracy than computed tomography. The limits of scintigraphy are the possibility of false-negatives in around 10% of patients whereas computed tomography visualizes more than 95% of intra-adrenal tumors.     

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.     

Peripartum hypertension from pheochromocytoma: a rare and challenging entity

BACKGROUND: Pheochromocytoma, a rare and usually curable cause of hypertension, is characterized by symptoms and signs related to increased catecholamine secretion. Pregnancy can elicit clinical manifestations of otherwise unrecognized pheochromocytoma. METHODS AND RESULTS: Four women, ranging in age from 27 to 37 years, were referred to the hypertension clinic with the following presentations: 1) a 35-year-old woman, diagnosed with gestational hypertension and headaches during the third trimester of her pregnancy and 5 months after delivery, was hospitalized with pulmonary edema. Echocardiography revealed severe dilated left ventricular (LV) dysfunction. Cardiac function was normalized after surgical resection of a pheochromocytoma from her left adrenal; 2) a 37-year-old woman suffered from preeclampsia, persistent hypertension and orthostatic hypotension after a cesarean section. A diagnostic work-up revealed a catecholamine-secreting paraganglioma in the retroperitoneum. The patient underwent a laparosopic resection of the tumor; 3) a 27-year-old woman suffered from hypertension and episodes of palpitations, sweating, and dyspnea in the first trimester of her pregnancy. An ultrasound revealed a 5-cm mass in the left adrenal. She underwent a left adrenalectomy at the 17th week of pregnancy, which confirmed the diagnosis of pheochromocytoma; 4) a 34-year-old woman, at the 26th week of pregnancy, presented with an acute loss of vision and blood pressure of 230/140 mm Hg. Fundoscopy showed papilledema with soft exudates in both eyes. Chemical studies were positive and imaging revealed a left adrenal pheochromocytoma. Despite aggressive medical treatment, fetal distress mandated a laparotomy at the end of the 28th week of pregnancy. A healthy newborn was delivered and resection of the adrenal tumor confirmed the diagnosis of pheochromocytoma. CONCLUSIONS: Although rare, pheochromocytoma can cause severe peripartum hypertension. Screening for pheochromocytoma, ideally with plasma-free metanephrines, should be considered in cases of peripartum hypertension.     

Reversible cerebral ischemia in patients with pheochromocytoma

Cerebral ischemia and symptoms of stroke can occur as a rare manifestation in patients with pheochromocytoma. We describe a 45-year-old woman who was admitted because of a right-sided hemiparesis due to an ischemic lesion in the left hypothalamus. The clinical diagnosis of a pheochromocytoma was proven by highly elevated urinary catecholamines and confirmed histologically after operation. The successful removal of the tumor led to the almost complete recovery of the neurological deficiencies. It is of vital importance to know this atypical presentation of pheochromocytoma. The diagnosis of pheochromocytoma should be suspected in patients with focal cerebral symptoms, particularly in the presence of intermittent hypertension or other paroxysmal symptoms suggestive of pheochromocytoma.     

Periodic fluctuation of blood pressure and its management in a patient with pheochromocytoma. Case report and review of the literature

The case of a 69 year old man with a right adrenal pheochromocytoma who manifested cyclic fluctuations of blood pressure with a cycle length of 9 to 13 min is reported. We collected and reviewed 14 similar cases previously reported in the literature. In these cases, right adrenal pheochromocytoma was most common, while 1 case involved the left adrenal and 2 cases were of extra-adrenal origin. The incidence in males was twice that in females and the median age was 45.3 years. Although a good correlation between the blood pressure and plasma norepinephrine concentrations was observed in our patient, the exact mechanism for the cyclic fluctuations of blood pressure is not known. In our patient, both YM-09538 and bunazosin were effective in controlling severe hypertension preoperatively. YM-09538 induced significant increases in urinary norepinephrine concentrations (1327 +/- 238 micrograms/day), while bunazosin induced a significant decrement in urinary norepinephrine concentrations (475 +/- 188 micrograms/day) compared with pretreatment levels (900 +/- 42 micrograms/day) (p less than 0.01). These observations indicated that bunazosin as a postsynaptic alpha-adrenergic receptor blocker interfered with release of norepinephrine from the tumor and thus might be beneficial in the management of elevated blood pressure in patients with pheochromocytoma.     

意外发现的42例嗜铬细胞瘤的临床特征

分析长海医院2001年至2009年诊断为嗜铬细胞瘤患者的临床资料,发现后4年中意外发现的嗜铬细胞瘤所占比例明显高于前5年,并且42例意外发现该病患者的高血压发生率、血压发作时最高收缩压、舒张压及平均动脉压显著低于有疑似症状患者.

Abstract：

We have retrospectively analyzed the medical files of 86 consecutive patients who were diagnosed as cases of adrenal or extra-adrenal pheochromocytoma at Changhai hospital between 2001 and 2009. Patients with incidentally detected pheochromocytoma often had lower prevalence of hypertension and lower mean arterial blood pressure compared with those patients suspected of pheochromocytoma on clinical grounds.     

Pheochromocytoma underlying hypertension, stroke, and dilated cardiomyopathy

We report the case of a 65-year-old man with a 6-year history of hypertension who presented with dilated cardiomyopathy, a transient cerebrovascular event, paroxysmal sweating, and intractable hypertension. Coronary angiography revealed no abnormality, but diagnostic testing was pursued because of the severe sweating and hypertension. Two-dimensional echocardiography showed 4-chamber dilatation with decreased left ventricular contractility. Further investigation, including a computed tomographic scan of the abdomen, led to a diagnosis of pheochromocytoma. Surgical resection of a left adrenal pheochromocytoma quickly resolved the patient's hypertension and resulted in substantially improved cardiac function after 4 months. Although pheochromocytoma has rarely been reported in the presence of both dilated cardiomyopathy and cerebrovascular events, it should be included in the differential diagnosis when patients present with dilated cardiomyopathy and a cerebrovascular event that have no obvious cause.     

Malignant pheochromocytoma.

We present an interesting case of paroxysmal hypertension in a young male caused by malignant pheochromocytoma. This patient, who had history of paroxysms of abdominal pain with severe hypertension, developed osseous metastasis in the first lumbar vertebra resulting in collapse of the vertebra and it caused paraplegia. The diagnosis of pheochromocytoma was confirmed on histopathology.     

Pheochromocytoma associated with adrenocortical tumor in the same gland. Two case reports and literature review

Pheochromocytomas are catecholamine-producing neuroendocrine tumours arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglionic system that show 2 distinctive features, rarity and clinical variability. Pheochromocytoma occasionally is associated with pathological lesions of the adrenal cortex. We present 2 cases of patients referred to our hospital with a finding of clinical suspected pheochromocytoma. Both of them were hypertensive; the first patient with typical symptoms of pheochromocytoma and the second patient with chest pain and hypertension resistant to pharmacological treatment. The diagnosis of pheochromocytoma was confirmed in both cases with laboratory analysis and the lesion was achieved by employing 3 imaging techniques: computed tomography (CT), magnetic resonance imaging (MRI) and scintigraphy with (123)I-metaiodobenzilguanidine (MIBG). The patients underwent adrenalectomy and in the same adrenal gland we found a pheochromocytoma associated with a nonfunctioning cortical adenoma. As far as we know few cases with this association are available in the literature.     

A pitfall of metaiodobenzylguanidine scan: paraganglioma in close proximity to adrenocortical adenoma.

We report a potential pitfall of 123I-metaiodobenzylguanine (MIBG) scan. Magnetic resonance imaging performed for other reasons, showed 2.5 cm tumor in the left adrenal gland. On questioning patient had episodic palpitations, flushing and hypertension suggestive of pheochromocytoma. Urinary metanephrine level was of borderline value but serum chromogranin A level was clearly elevated. 123I-MIBG scan showed accumulation of the tracer in the upper left abdomen and the finding was suspected to be intra-adrenal pheochromocytoma. During operation two separate tumors, adrenocortical adenoma in the left adrenal gland, and another smaller, extra-adrenal paraganglioma locating very close to the adenoma, were found. Thus the positive MIBG finding was caused by a paraganglioma with the concurrent presentation of nonfunctioning adrenocortical adenoma.     

Role of adrenocortical scintigraphy in the exploration of incidentally discovered tumors]

To determine the utility of adrenocortical scintigraphy with I131-6 beta-iodomethyl-19-nor-cholesterol (NP59) in incidentally discovered adrenal masses, we studied 12 patients with a unilateral adrenal mass and without other primary tumors or signs of pheochromocytoma or hyperfunctioning adenoma. Ten patients had an adenoma (size: 12 to 35 mm), the diagnosis was made by surgery or by no change in size on repeated CT scans. The NP59 scintigraphy showed an increased uptake on the side of the tumor in 8 cases with a decreased uptake of contra-lateral gland in 7 cases. Hormonal investigations of glucocorticoid function suggested supranormal or fluctuant cortisol secretion in 5 cases as assessed by moderately elevated urinary free cortisol or by incomplete dexamethasone suppression test. These abnormalities disappeared after surgery. Two patients had normal bilateral uptake of NP59, the sizes of the tumors were 12 and 20 mm. Two patients had an extra-adrenal tumor. The NP59 scintigraphy showed a moderately decreased uptake on the side of the hematoma of one patient and a compression of the normal adrenal by ganglioneuroma of the other patient. Our results and those of other authors suggest that positive NP59 scintigraphy could confirm the cortical nature of an incidentally discovered adrenal mass, probably an adenoma that must be followed up morphologically and functionally. No uptake by a tumor greater than 2 cm suggests a primary malignancy or extra-adrenal origin which must be diagnosed by invasive methods.     

Pontine hemorrhage in a patient with pheochromocytoma

A 24-year-old woman with a two-year history of hypertension was hospitalized for coma and quadriplegia secondary to pontine hemorrhage. A seven-year history of intermittent severe headaches, diaphoresis, and anxiety together with persistent severe hypertension led to the diagnosis of pheochromocytoma. This unusual but devastating manifestation of pheochromocytoma illustrates the importance of excluding remedial forms of hypertension in young patients before initiating antihypertensive therapy.     

Weight-loss with activation of brown fat: Suspect pheochromocytoma

IntroductionExcess catecholamine stimulates heat production in brown adipose tissue (BAT). Activation of BAT can be detected in patients presenting pheochromocytoma.Case studyA 58-year-old female patient sought medical advice due to 13 kg weight loss over 2 years accompanied by sweating and high blood pressure. Thoracic-abdominal-pelvic CT-scan revealed a solid 40 mm mass in the left adrenal compartment with peri-adrenal nodules and a solid 80 mm mass at the lower end of the right kidney. ¹⁸FDG-PET scan exhibited intense uptake in the supraclavicular, intercostal, mediastinal, peri-renal, mesenteric, iliac and inguinal spaces. Renal tumor with locoregional infiltration and remote metastases was initially considered. Diagnosis of pheochromocytoma was subsequently confirmed by a 10-fold increase in urinary catecholamine, metanephrine and normetanephrine levels. Left adrenalectomy confirmed the diagnosis of pheochromocytoma, with 3 lymph-node metastases in the adjacent adipose tissue surrounded by brown fat. The patient was clinically asymptomatic with normal blood pressure at 3 months post-surgery. A weight gain of 6 kg was recorded, with normalisation of catecholamines/metanephrine/normetanephrine levels. Bilateral peri-renal infiltration (including the right renal mass) disappeared on CT-scan, and TEP-18-FDG no longer showed hypermetabolism. Recurrent mediastinal metastases were diagnosed 6 months after surgery.ConclusionBrown fat activation may mislead diagnosis of pheochromocytoma, suggesting multi-metastatic extra-adrenal tumor, if clinicians are not aware of it.     

Diffuse uptake of brown fat on computed-tomography coupled positron emission tomoscintigraphy (PET-CT) for the exploration of extra-adrenal pheochromocytoma

We report an observation of strong bilateral uptake on a PET-CT scan compatible with activation of brown adipose tissue in a patient with extra-adrenal pheochromocytoma. A 42-year-old man was hospitalized for hypersudation together with weight loss and palpitations. Heart rate was 120 bpm and fasting blood glucose 1.36 g/l. Endocrine explorations revealed elevated serum chromogranine which reached 517 ng/ml (19-38). The norepinephrine level reached 49.7 nmol/l (<4.00) and urinary norepinephrine and normetanephrine levels reached 13977 nmol/24h (<414) and 32 micromol/24h (0.4-2.5) respectively. The thoraco-abdominal and pelvic scan showed a 6 cm diameter paraaortic hypervascularized mass with an infiltrative lesion of both perirenal area and mediastinal tissue without adenopathies. The abdominal MRI revealed the mass with a low intensity signal in T1 and a slight high intensity signal in T2. MIBG and octreoscan scintigraphies were negative. 18F-DG PET showed intensed uptake in the tumor mass together with intense, diffuse and bilateral uptake above and below the diaphragm. The mass was resected. Histological examination of the surgical specimen confirmed the diagnosis of extra-adrenal pheochromocytoma with an index of 13% cellular proliferation without cell atypia. There was a hypervascularization with small islets of brown adipose tissue in the perirenal fat. Both plasmatic and urinary catecholamines decreased to the normal range after the operation and PET-scan normalized. Bilateral spread of the radiotracer uptake was probably due to brown adipose tissue activation by excessive sympathetic stimulation induced by catecholamines released by the tumor.     

Malignant pheochromocytoma. Apropos of a case report

Pheochromocytoma was diagnosed in a male of 38 on the basis of severe and progressive hypertension associated with marked increases in urinary catecholamines and vanilmandelic acid. Left extra-adrenal topography was examined by tomography and confirmed by surgical treatment involving exeresis of the primary tumor and the metastatic latero-aortic lymph nodes, thus corroborating the diagnosis of malignancy. Complementary post-operative radiotherapy was performed on the abdomen. Eighty months later the patient is making good progress.