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Unlabelled: We assessed the performance of a new serum chromogranin A (CgA) assay in combination with the results of (131)I-metaiodobenzylguanidine (MIBG) scintigraphy for diagnosis and follow-up in 89 patients with clinical findings suggestive of pheochromocytoma., Methods: The study population consisted of 41 patients with proven pheochromocytoma and 48 patients with refuted pheochromocytoma. Eighty-seven scintigraphy examinations were performed, 52 in patients with proven pheochromocytoma (39 before surgery and 13 after surgery) and 35 in patients with refuted pheochromocytoma., Results: The sensitivity of the CgA level was 90.2%, and the specificity was 99.0% and 92.3% in the control and refuted pheochromocytoma groups, respectively. A significant relationship was seen between serum levels of CgA and tumor mass (r = 0.70; P < 10(-5)). The postoperative CgA level was an early and accurate predictor of curative surgery or relapse. The concordance between CgA levels and scintigraphic data was 90.8%., Conclusion: Serum CgA level is an effective marker of pheochromocytoma. Increased levels strongly correlate with tumor mass; therefore, small tumors may go undetected. The concordance between CgA level and the results of (131)I-MIBG scintigraphy is high. A CgA level in the reference range is highly predictive of normal scintigraphy findings.

We report the occurrence of a sustained hypotension (vasoplegia) following thoracic phaeochromocytoma surgery. Diagnosis of spinal cord injury was done by magnetic nuclear resonance (MNR) showing surgical "Horsley wax" inside the vertebral canal and ischaemic signal inside the anterior part of the spine cord. Removal of "Horsley wax" dramatically improved arterial blood pressure but did not correct all neurologic disorders. Haemodynamic disorders related to spinal cord injury are rare after thoracotomy, and may have been enhanced by the haemodynamic instability typically associated with phaeochromocytoma surgery. Early diagnosis has to be done by MNR.

Evaluation of the malignant potential of phaeochromocytomas in the absence of metastases presents a formidable challenge to both clinicians and pathologists. Until now, no widely accepted clinical, histological, immunohistochemical or molecular method has become available to discriminate malignant from benign phaeochromocytomas. In other endocrine tumours, estimation of proliferative activity by MIB-1 immunostaining has emerged as a promising approach for the determination of metastatic potential. In this study, the utility of MIB-1 immunostaining as a predictive marker for the occurrence of metastases in phaeochromocytomas was evaluated. In addition, the density of S100-positive sustentacular cells was studied, since their depletion has been identified as a negative predictive marker in smaller series. Furthermore, several clinicopathological parameters were evaluated. One hundred and ten patients operated on for a total of 99 benign and 37 malignant phaeochromocytomas were studied. All malignant tumours had documented metastases. The histopathological diagnosis of primary tumours and metastases was reviewed and graded for angioinvasion, capsular extension, and intra-tumoural necrosis. The proliferative index (percentage of MIB-1-positive cells) and the density of S100-positive cells were assessed. In addition, age at resection, associated familial tumour syndromes, tumour size, and tumour location were recorded. Univariate analysis revealed statistically significant correlations between malignancy and proliferative index (p<0.0005) and depletion of S100-positive sustentacular cells (p<0.0005). Fifty per cent of the malignant, but none of the benign phaeochromocytomas had a proliferative index greater than 2.5%. Higher age at resection (p=0. 03), sporadic occurrence (p<0.0005), extra-adrenal location (p<0. 0005), tumour size (p<0.0005), and necrosis (p=0.03) were also significantly associated with malignancy. Logistic regression showed that proliferative index (p=0.0072), size (p=0.0022), and extra-adrenal location (p=0.0012) of the primary tumour were independently predictive for malignancy. In conclusion, this study indicates that assessing the proliferative activity of phaeochromocytomas by MIB-1 immunohistochemistry can predict the occurrence of metastases. The predictive value of S100 immunostaining, tumour size, and extra-adrenal location of the tumour was also confirmed., (Copyright 2000 John Wiley & Sons, Ltd.)

Somatic mutations in the RET proto-oncogene are involved in the pathogenesis of an important subset (40-60%) of sporadic medullary thyroid carcinomas (MTCs) and less frequently (0-31%) in benign, sporadic phaeochromocytomas. Since limited data exist regarding the significance of somatic RET mutations in malignant phaeochromocytomas, we analysed a multicentre series of proven malignant (i.e., metastasised) phaeochromocytomas. Analogous with MTCs, where RET mutations lead to an aggressive behaviour, we hypothesised that somatic mutations would occur more frequently in malignant than in benign phaeochromocytomas. Paraffin-embedded tissue was available from 29 malignant and 27 benign phaeochromocytomas. Exons 10, 11 and 16 were analysed by non-radioactive single-strand conformation polymorphism, heteroduplex gel electrophoresis, restriction enzyme digestion and aberrant band patterns by non-isotopic sequencing. In only 1 of 29 malignant phaeochromocytomas was a mis-sense mutation found (at codon 634 of exon 11), whereas in 15% (4/27) of the benign tumours a point mutation was detected (in 3 tumours in exon 16 at codon 918 and in 1 tumour in exon 10 at codon 618). Absence of these mutations in non-tumourous DNA proved their somatic origin. Contrary to what has been reported for MTCs, oncogenic RET mutations are not associated with an aggressive tumour behaviour in sporadic phaeochromocytomas.

Background: Adrenal incidentaloma poses a perplexing problem for physicians. The challenge is to identify the rare functioning or malignant adrenal tumor that should be removed., Patients and Methods: From 1970 until December 1996, we managed 579 patients with adrenal hyperplasia or neoplasm. Of these, 110 were followed without any operation and 469 were operated on. The histology from the operated patients revealed 145 pheochromocytomas, 72 Cushing's syndrome, 98 aldosteronomas, 21 virilizing tumors, 3 feminizing tumors, 98 non-functioning adrenalomas, 17 metastases, 7 cysts, and 15 miscellaneous tumors., Results: Among the 98 non-functioning adrenal tumors, 79 were incidentalomas. Histological examination of 103 operated incidentalomas found 55 adenomas (5 functioning=aldosteronomas), 12 benign pheochromocytomas, 3 malignant or suspicious pheochromocytomas, 8 cystic lymphangiomas, 4 metastases, 4 angiomas, 3 ganglioneuromas, 4 myelolipomas, 1 hyperplasia, 2 hematomas, 2 cysts, and 5 adreno-cortical carcinomas. Among the non-operated incidentalomas, the most frequent findings were adenomas, metastases, hematomas, cysts and pseudotumoral hyperplasia; three disappeared spontaneously. No patients died of unrecognized adrenocortical carcinoma., Conclusion: Our experience confirms that in case of incidentaloma, the first concern is a nonfunctional pheochromocytoma (15%), and the less common occurrence is adreno-cortical carcinoma (2%). We recommend a restrictive surgical approach in the setting of adrenal incidentalomas.

The pre and intraoperative use of calcium channel blockers (CCB) has been suggested for the management of either eutopic or ectopic pheochromocytomas. We report our experience of 70 pheochromocytomas, operated between 1988 and 1996 and managed with CCB, especially nicardipine. 59 were hypertensive (84.2%). Preparation consisted of nicardipine in 61 patients or another CCB in 9 cases with duration ranging from 24 hours to several weeks depending on plasma volume and blood pressure control. Intraoperatively, nicardipine infusion was started after intubation, adjusted according to systolic blood pressure (SBP) and stopped before ligation of the tumor venous drainage. Increases in SBP greater than 200 mmHg were observed in 10 patients and were effectively controlled by nicardipine in all cases. In 16 patients, the S > BP remained less than 150 mmHg throughout anesthesia. Heart rate greater than 100 b p m occureed in 51 patients and was easily controlled with esmolol whenever used (n = 27). Arythmias were unfrequent (n = 4) and required treatment in only one case. This study confirms the ability to adequately manage pheochromocytomas with the use of nicardipine as sole vasodilating agent.

The perioperative mortality related to cardiovascular complications has been almost completely eliminated in phaeochromocytoma surgery. The anaesthetic management has mainly evolved through refinements in haemodynamic control during the operation. Neither preoperative preparation nor general anaesthesia can totally prevent haemodynamic disturbances during surgical manipulation of the tumour or after removal of the tumour. General anaesthesia, with high doses of opioids, remains the most usual technique. Intraoperative monitoring should include an arterial catheter and a pulmonary arterial catheter. Although a number of antihypertensive drugs have been tested, the preventive use of nicardipine i.v. may provide a simple and effective haemodynamic control. Esmolol, an ultrashort acting agent, ensures a dose-related cardiac beta 1-blockade. It is used for the treatment of arrhythmia and cardiac adrenergic stimulation, which causes tachycardia and increases cardiac output. Volume loading is recognised as the treatment of choice for hypotension following tumour removal. During the postoperative period, the great hazard is hypoglycaemia, and plasma glucose levels should be monitored over the immediate postoperative hours.

Background: von Hippel-Lindau disease is an autosomal dominant disorder characterized by the development of hemangioblastomas in the cerebellum, spinal cord, and retina, renal cell carcinoma and cysts, pancreatic cysts, and pheochromocytoma., Methods: We have studied a series of 36 French patients affected with von Hippel-Lindau disease pheochromocytoma. Thirty (83%) of them were diagnosed as having von Hippel-Lindau disease because the disease occurred in a familial von Hippel-Lindau disease setting; six (17%) were diagnosed as having von Hippel-Lindau disease because they displayed another characteristic manifestation of that disease., Results: The mean age at pheochromocytoma diagnosis was 29 +/- 14 years (5 to 62 years). Bilateral tumors were documented in 15 (42%) cases, paraganglioma was associated with adrenal pheochromocytoma in four cases, and malignant pheochromocytoma occurred in three cases. Prevalence of pheochromocytoma revealing von Hippel-Lindau disease was 20 (53%) out of 36. In six cases pheochromocytoma was the only manifestation of the disease., Conclusions: In the interest of the patients themselves and of family members who are at risk, search for von Hippel-Lindau disease must be systematic in the presence of pheochromocytoma. Basic checkup may be completed with familial inquiry, ophthalmoscopy, cerebral magnetic resonance imaging, abdominal ultrasonography, and computed tomography-scan for detection of latent lesions. In the future, after characterization of von Hippel-Lindau disease gene mutations, molecular diagnosis is going to be possible in individual patients.

Distant metastases are the only clue for diagnosis of malignancy in pheochromocytoma patients. This study was designed to define a secretory profile possibly suggestive of malignancy. Among 79 pheochromocytomas (55 benign, 24 malignant), dopamine-secretion, either exclusive or blended with other catecholamines was found in 34.5% of benign and in 75% of malignant tumors. Dopamine secretion, although if more frequent and more abundant in cases of malignant pheochromocytomas, is therefore not actually diagnostic, but only suggestive of malignancy. It demands life-long follow-up as metachronous metastases may supervene extremely late in the course of the disease.

In this surgical series of 100 pheochromocytomas (PH), where 91 cases were studied and followed up, the frequency of malignancy appears high (29%) on macroscopic criteria observed at the first operation (25 out 26 cases of malignant PH) or thanks to the occurrence of metastases (1 case out of 26 malignant PH). While some clinical signs are suggestive, there is no excretory profile predictive of malignancy. Isolated or predominant secretion of dopamine is not specific of malignancy event if it occurs more frequently and severely in malignant PH. Bilateral involvement, occurring in the setting of phacomatosis or of multiple endocrine neoplasia (MEN II), or in a sporadic case, is not a predictor for malignancy. Contrarily, extraadrenal involvement is a major feature indicative of malignancy. A CT scan which demonstrates possible locoregional invasion, and a MIGB scan revealing distant localizations raise the suspicion of malignancy. The preferred surgical approach is via a laparotomy, thus allowing the exploration of all possible abdominal chromaffin site and the search for intraabdominal metastases. Intraoperative MIBG scanning checks the completeness of the excision. Flow cytometric DNA ploidy studies have been performed in 25 of our patients. The follow up of benign or malignant PH, after excision "for cure" must be life-long: clinically, biologically and by MIGB scan. Persistence of the disease after surgery or recurrence with unresectable metastases can benefit from MIGB and chemotherapy.

Von Hippel-Lindau (VHL) disorder is an autosomal dominant disease characterized by the almost constant development of hemangioblastomas in the central nervous system (cerebellum, spinal cord and retina). In addition, various types of tumors including renal cell carcinomas, pancreatic cysts and pheochromocytomas are frequently observed in VHL gene carriers. Linkage of the VHL locus to the RAF-1 oncogene on the short arm of chromosome 3 (3p25-26) has been recently reported. Pheochromocytoma is of particular interest because of the risk of inaugural malignant hypertensive crisis but especially because of a great degree of interfamily variability (from 0 to 92% of affected members in previously reported large kindreds). We have studied a French series of 25 pheochromocytoma (11 males, 14 females) in VHL affected patients. Twenty pheochromocytoma (80%) occurred in a familial context, whereas 5 (20%) were consistent with "apparent sporadic cases". The mean age at pheochromocytoma diagnosis was 27 years (5-55 years). Bilateral tumours have been documented in 13 cases (52%). The prevalence of pheochromocytoma revealing VHL was 14 out 25 (56%). In these cases, VHL diagnosis was considered up to 25 years later. In 6 cases (2 deceased) pheochromocytoma was the only manifestation of VHL. Thus, search for VHL must be systematic in the presence of pheochromocytoma, in the interest of the patients themselves and of potential at-risk family members (prevention of hypertensive crisis linked to latent tumours). Basic check-up (neurological and somatic examination, ophthalmoscopy, familial inquiry) may be completed with cerebral CT scan or MRI and abdominal ultrasonography followed, if positive or doubtful, by abdominal MRI or selective angiography.

In a 20 year period, from 1971 through 1991, 105 chromaffin tumours--excluding cervical ones--were operated by the same surgeon: 50 during the first 15 years and 55 during the last 5 years. Pheochromocytomas are defined as intra-adrenal chromaffin tumours, and paragangliomas--or ectopic pheochromocytomas--as of extra-adrenal location. Among those tumours, 30 were malignant (i.e. metastatic) and 75 benign. Among the 30 malignant tumours, 14 were ectopic, 2 occurred in a MEN II A setting and were bilateral, 2 were associated with liver adenoma and liver hemangioma respectively suggesting Von Hippel-Lindau syndrome, and one case was associated with a seemingly sporadic primary hyperparathyroidism. 9 out of those 30 malignancies were not associated with hypertension. Among 75 benign pheochromocytomas or paragangliomas, 10 were ectopic, 7 occurred in a MEN setting (6 type II, 1 type I). 3 patients without evidence of MEN or other neuroectodermal abnormalities presented bilateral pheochromocytoma, either synchronous (2) or metachronous (1). 7 cases occurred in a Von Hippel-Lindau syndrome (3 bilateral) and 4 in a neurofibromatosis setting (1 bilateral). 3 other cases were familial without evidence of MEN (including a case of triple tumour: bilateral and ectopic and another ectopic case). 2 other cases were associated with seemingly sporadic hyperparathyroidism. As a whole, in 34 of 75 benign pheochromocytomas or paragangliomas, the tumour was not intra-adrenal, unilateral and sporadic. Among those 75 tumours, 22 were not overtly hypertensive, including 10 out of the 41 seemingly intra-adrenal, solitary and sporadic. The pheochromocytoma, benign, intra-adrenal sporadic, hypertensive accounts for no more than 30% of the subphrenic catecholamine-secretin chromaffin tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the case of a young patient of 37 presenting with two attacks of pulmonary oedema which revealed an underlying pheochromocytoma. The diagnosis was suggested by the raised level of vanyl-mandelic acid in the urine and the abdominal CT scan. After an adrenalectomy the outcome was satisfactory. Pheochromocytoma should be considered in the differential diagnosis of the acute respiratory distress syndrome in the adult linked to the action of the circulating catecholamines on the pulmonary capillaries.

Alpha-methyl-paratyrosine (Demser) is a specific inhibitor of tyrosine hydroxylation to dopa. It is administered orally and may be given in combination with symptomatic treatments to reduce the hypersecretion of catecholamines. We report two cases of malignant phaeochromocytoma in which this drug was used. A pharmacological study of the compound is presented, and the literature on its long-term use in the treatment of malignant phaeochromocytoma is reviewed. In our second patient, who received alpha-methyl-paratyrosine for 9 months, a study of changes in differential catecholamine excretion showed that the urinary catecholamines were redistributed, with an increase in the dopamine/norepinephrine ratio. An HPLC study of urinary excretion of catecholamines demonstrated that their levels cannot be significantly increased by excretion of alpha-methyl-paratyrosine or its metabolites.

The authors have observed a case of phaeochromocytoma revealed by fever and poor general condition without hypertension. Urinary catecholamine assays showed predominant dopamine secretion. Only 13 cases of dopamine-secreting phaeochromocytoma have been published so far, including 4 with clinical symptoms resembling those of this patient. The metabolic and hormonal effects of high plasma dopamine levels were studied, and responses similar to those observed with TRH stimulation by dopamine infusions were obtained: TSH and prolactin responses were inhibited, and GH was increased. This case underlines the need for catecholamine assays, including dopamine, in patients with unexplained fever and apparently non-secretory adrenal tumour.

This study investigates the role of nicardipine hydrochloride in preoperative and intraoperative blood pressure control and intraoperative catecholamines (norepinephrine and epinephrine) release in 10 patients undergoing pheochromocytoma resection. Nicardipine was used orally in the preoperative period for either 1 or 8 days (60 to 120 mg/24 hr) and then was infused during anesthesia until tumor removal, continuously at a rate of 2.5 to 7.5 micrograms/kg/min, depending on systolic arterial pressure level. All patients were successfully operated on. No severe hypertensive crisis occurred during tumor manipulation, although several patients had a 3- to 85-fold (norepinephrine) and 3- to 40-fold (epinephrine) increase of catecholamines from baseline levels. Hemodynamics data suggest that nicardipine caused significant inhibition of vascular smooth muscle contraction (42% decrease in systemic vascular resistance); calcium-dependent catecholamines release was not inhibited by nicardipine infused as mentioned. Use of nicardipine may be recommended for perioperative and intraoperative control of pheochromocytomas and might substitute for routine alpha-adrenergic blockade.

Studies were conducted in 14 patients with pheochromocytoma over a 3-year period. Circumstances of detection of these tumors varied greatly and were sometimes misleading, hypertension being an inconstant finding in the clinical history and was not always the predominant feature. Biologic exploration involved assay of excretion of free urinary noradrenaline (NA), adrenaline (AD) and dopamine (DA) using a HPLC technique as well as assay of total methoxy derivatives and urinary vanilmandelic acid. Validity of each assay in the diagnosis of pheochromocytoma could be evaluated and only the total free methoxy derivatives gave false negative results. Hormonal secretion of pheochromocytoma is often mixed, but sometimes predominant or exclusive for a single catecholamine. Relative increases of the different catecholamines, evaluated from the ratios DA/NA and DA/NA + AD, are an important factor since a relation exists between blood pressure induced symptomatology and equilibrium between hypotensive hormone (DA) and pressor amines (NA + AD); 3 types of pheochromocytoma can be described: NA-induced with paroxysmal or permanent hypertension but without typical metabolic and cardiac disorders, and with a very reduced DA/NA + AD ratio during hypertensive crises; AD-induced without permanent hypertension but with a mainly orthostatic hypotension and episodes of cardiovascular collapse following hypertensive attacks and with an AD/NA ratio greater than 1; finally the DA-induced lesion in which hypertension is never associated and manifestations are misleading and atypical with an elevated DA/NA + AD ratio.

Between 1971 and 1987, 60 patients presenting 68 pheochromocytomas were operated on in the University Teaching Hospital of Lille. Diagnosis has been transformed by the use of CT scan, which for the last 10 years has enabled the lesion to be more reliably localized than by MIBG scintigraphic scanning. Combination of the two investigations enables the diagnosis to be confirmed in 100% of cases. The following topics are covered: preparation for surgery with the indications for alpha and beta blockers, route of approach--preferably median laparotomy--and operative sequelae as a function of the benign or malignant nature of the tumor.

A pheochromocytoma that exclusively secretes dopamine (DA) rather than predominantly DA among a blend of catecholamines is as yet unreported. Of the 50 patients with pheochromocytoma who have undergone surgery, 32 underwent treatment within the last 5 years (when DA assay has been available). One half of these patients (15/32) exhibited DA secretion either in mixed catecholamines (12 patients) or exclusively (three patients). All three patients with exclusive DA-secreting tumors were normotensive. Without hypertension, the clinical investigation was a diagnostic challenge (unexplained cough or flank mass with inflammatory features). All three tumors were malignant and two were ectopic. Five of the 12 patients with mixed catecholamine-secreting tumors whose secretions included DA were hypertensive. Five other patients had flank mass and one had an unexplained cough. Tumors were rather large, and three of the tumors with mixed secretion were ectopic. Of the 12 patients, seven had tumors that were judged to be malignant. Three patients exhibited a dramatic decrease in blood pressure under alpha-blockade, which was not used in subsequent cases. Predominant or exclusive secretion of DA would explain the lack of hypertension due to its antiadrenergic action that inhibits the vasoconstrictive effects of other amines. Hypertension in patients with pheochromocytoma might depend on the ratio of DA/noradrenaline + adrenaline.

After having reported the case of a pheochromocytoma associated to Recklinghausen's disease, the authors define the best criteria of detection and localization of the pheochromocytoma and study its association to phacomatoses. Headaches, bouts of tachycardia and excessive inappropriate diuresis are the most evocative clinical signs of a pheochromocytoma. The different hormones and their urinary metabolites must be titrated separately and repeatedly. Two other examinations, scanner and scintigraphy with MIBG, visualize quite reliably the tumor foci. Calcium inhibitors are quite effective in sudden blood pressure rises. The association described here, may be explained by the fact that the two pathologies belong to the group of neurocristopathies.

Study of 20 pheochromocytomas in 19 patients confirmed the remarkable sensitivity of computed tomography (100%) for the detection of their adrenal and juxtarenal localizations. However, ultrasonography was as effective as the CT scan in these same patients, and even detected latent tumors in several cases. Certain pheochromocytomas in this series presented unusual appearances, particularly two large tumors which were manifest as abdominal masses and a malignant form which provoked a total infarct of the homolateral kidney.