Outcomes of adrenalectomy in patients with unilateral primary aldosteronism: a review.

Aldosterone hypersecretion in primary aldosteronism is unilateral (aldosterone producing adenoma and primary unilateral hyperplasia) or bilateral (idiopathic adrenal hyperplasia). Laparoscopic adrenalectomy is nowadays the preferred approach to treat patients with unilateral primary aldosteronism. We review the outcomes of this intervention in recently published series. Laparoscopic adrenalectomy has a morbidity of 5-14%, mortality below 1%, and a mean hospital stay around 3 days. It generally results in the normalization of aldosterone secretion and in a large decrease of blood pressure and antihypertensive medication, but normotension without treatment is only achieved in 42% of all cases. Normotension following adrenalectomy is more likely in young and lean women with recent low grade hypertension than in obese men with long-standing high grade hypertension or a family history of hypertension. However, individual prediction of the blood pressure outcome is not accurate and predictors of hypertension cure should not be used to select patients for surgery. Age, associated health conditions and preferences of the patient are more relevant to this end.

Long-term postoperative follow-up in patients with apparently benign pheochromocytoma and paraganglioma.

Patients with pheochromocytoma or paraganglioma are at risk of developing tumor recurrences or new tumors after successful resection of the primary tumor. This review summarizes current knowledge concerning the incidence and risk factors for such events. The overall incidence exceeds 15%. Patients with inherited tumors have a higher probability of recurrence or new tumors. Most recurrences are metastatic, particularly in patients with SDHB mutations or nonhereditary tumors. We recommend the determination of plasma or urinary metanephrines (normetanephrine and metanephrine) 1 month after surgery. In patients with sporadic, single tumors ≤5 cm in diameter, clinical and biochemical follow-up should be performed every 2 years. However, this follow-up period can be reduced to yearly, if it is more simple and more convenient for patients and physicians. Patients with larger or multiple but apparently benign tumors and/or inherited disease should be tested 6 months after surgery and then every year for the rest of their lives. Imaging follow-up is also required in patients with inherited or malignant tumors.

Metastatic pheochromocytoma and paraganglioma: focus on therapeutics.

Metastatic pheochromocytomas and paragangliomas are rare and challenging tumors. The tumor burden, combined with excessive catecholamine production, predispose to a broad spectrum of complications that range from spinal cord compression to any organ damage, all of which may lead to decreased quality of life and overall survival. Current therapies include surgery, systemic chemotherapy and radiopharmaceutical agents. Surgery is often a preferred therapy because it may cure or allow a long-term remission in patients with locoregional or isolated resectable distant metastases. Additionally, surgery can palliate symptoms related to tumor burden or catecholamine excess. However, in patients for whom surgery is not an option, systemic chemotherapy and radiopharmaceutical agents are preferred options. Systemic chemotherapy and radiopharmaceutical agents such as 131I-Metaiodobenzylguanidine (131I-MIBG) may cause partial responses or stabilization of disease with better blood pressure control and symptomatic and performance status improvement. However, as these therapies are only palliative, patients' quality of life and personal preferences should always be considered. The recognition of molecular pathways involved in the pheochromocytoma and paraganglioma tumorigenesis has driven the development of new therapeutic options. Agents such as tyrosine kinase, MAPK, PI3K, or hypoxia inducible factor inhibitors, alone or in combination, may represent novel therapeutic strategies that could be evaluated in prospective clinical trials. Transcriptional profiling and the development of personalized cancer medicine will help to pave the way for more specific therapeutic approaches and combinations.

Catheter-based radiofrequency renal-nerve ablation in patients with resistant hypertension.

This review aims to describe the role and the results of catheter-based renal nerve ablation for the treatment of resistant hypertension. Despite the availability of multiple classes of orally active antihypertensive treatments, resistant hypertension remains an important public health issue in 2012 due to its prevalence and association with target-organ damage and poor prognosis. The failure of purely pharmacological approaches to treat resistant hypertension has stimulated interest in invasive device-based treatments based on old concepts. In the absence of orally active antihypertensive agents, patients with severe and complicated hypertension were widely treated by surgical denervation of the kidney until the 1960s, but this approach was associated with a high incidence of severe adverse events and a high mortality rate. A new catheter system using radiofrequency energy has been developed, allowing an endovascular approach to renal denervation and providing patients with resistant hypertension with a new therapeutic option that is less invasive than surgery and can be performed rapidly under local anaesthesia. To date, this technique has been evaluated only in open-label trials including small numbers of highly selected resistant hypertensive patients with suitable renal artery anatomy. The available evidence suggests a favourable blood pressure-lowering effect in the short term (6 months) and a low incidence of immediate local and endovascular complications. This follow-up period is, however, too short for the detection of rare or late-onset adverse events. For the time being, the benefit/risk ratio of this technique remains to be evaluated, precluding its uncontrolled and widespread use in routine practice.

Salivary aldosterone as a diagnostic aid in primary aldosteronism.

Recent evidence demonstrates an increased incidence of primary aldosteronism (PA) in approximately 10% of the hypertensive population, making noninvasive and simple screening methods necessary. The aim of the present study was to apply a time-resolved fluorescence immunoassay for the measurement of aldosterone in saliva and the establishment of a cut-off to identify patients with a high likelihood for PA requiring subsequent screening with the aldosterone to renin ratio. Saliva was collected (AM and PM) to ascertain an optimum time with best discriminating power between healthy and disease states. Plasma aldosterone, after overnight recumbency and 4 h later, was collected for posture testing. The participants included 53 PA patients (aged 14-78), 54 with essential hypertension (EH, aged 19-82), and 38 healthy volunteers (aged 19-56). Saliva aldosterone (SA) (median, 25-75(th)%) in PA was found at 90 pg/ml (61-139) compared to 53 pg/ml (40-85) in EH, with discrimination between PA versus EHs best in the morning (cutoff: 81 pg/ml, 77% sensitivity, 82% specificity). Saliva aldosterone decreases throughout the day in patients with adenomas [APA AM: 123 pg/ml (92-213) vs. PM: 79 pg/ml (41-116)], but not in those with bilateral hyperplasia [BAH AM: 85 pg/ml (59-115)] vs. pm 69 pg/ml (57-114). Morning SA alone allows discrimination between PA and controls, though with significant overlap against EHs, leading to a high number of false positives. More promising is the use of diurnal variation in SA in distinguishing between APA and BAH. The decline in SA seen in patients with APA presents a more constant finding compared to posture testing, which fails to correctly classify a large number of patients.

Treatment of malignant pheochromocytoma.

Pheochromocytoma (PCC) is a rare disease, mainly sporadic, but also associated with some familial disorders, with a malignancy frequency of approximately 10%. Only the presence of distant metastases, derived from large pleomorphic chromaffin cells, is widely accepted as a criterion of malignancy. Variable symptoms may be caused by production and release of catecholamines. Since there is no curative treatment for malignant PCC and due to its unfavorable prognosis, assuring quality of life is one of the main therapeutic objectives. Besides a long-term medical treatment of symptoms using selective alpha-1 blockers and nonselective, noncompetitive alpha- and/or beta-blockers, debulking surgery is the first treatment step. In case of a sufficient uptake of (123)I-MIBG treatment with targeted radiation therapy, use of (131)I-MIBG is an option as an adjuvant therapy, following debulking surgery. Chemotherapy should be applied to patients without positive MIBG-scan, with no response to (131)I-MIBG or progression after radionuclide treatment, and especially in cases with high proliferation index. The most effective chemotherapy regimen appears to be the CVD-scheme, including cyclophosphamide, vincristine, and dacarbazine. The so-called targeted molecular therapies with treatment combinations of temozolomide and thalidomide, or sunitinib monotherapy, and novel therapeutic somatostatin analogues have shown promising results and should thus encourage clinical trials to improve the prognosis of metastatic PCC. Within this review the current treatment modalities and novel molecular strategies in the management of this disease are discussed and a treatment algorithm is suggested.

[From clinical observation to assessment of practices: guidelines for hypertension management]. / De l'observation clinique à l'évaluation des pratiques : les recommandations pour la prise en charge de l'hypertension artérielle.

Arterial hypertension is highly prevalent and one of the main risk factors for cardiovascular diseases. It has been demonstrated that antihypertensive treatment is effective to prevent cardiovascular events. Advances have been made in this field for 50 years and the knowledge and management of hypertension has been modified continuously with increase of related costs. Therefore hypertension is one of the favorite themes for guidelines and indeed several guidelines have been published on this theme regularly. Despite this, a high percentage of treated hypertensive patients remains uncontrolled. Several reasons have been raised for not implementing guidelines: these guidelines are often little-known because of their large number and their bad distribution. A systematic analysis of the last guidelines showed also they were structurally different with a small percentage of identical references and they provided sometimes different practical conclusions. Finally, clinical inertia is partly responsible for these insufficient results. As the current form of the guidelines has a limited impact on the medical practice, we should find other methods to improve their implementation.

[Antihypertensive drugs prescribed to patients before their first consultation in a hypertension unit: comparison between 2001 and 2006]. / Traitement antihypertenseur prescrit aux patients avant leur première consultation dans un service spécialisé : comparaison entre 2001 et 2006.

PURPOSE: To determine if trends in antihypertensive drug prescriptions by non-specialist physicians reflect evidence from clinical research. METHODS: Comparison of antihypertensive drugs prescribed to patients before they attended a hypertension clinic in 2001 and 2006, with a special consideration for thiazide diuretics in drug combinations and angiotensin converting enzyme inhibitors (ACEI) in hypertensive patients at high cardiovascular risk (diabetes or secondary prevention). RESULTS: Overall, 1072 hypertensive patients attended the hypertension clinic in 2001 (mean age 53.9 years) and 1040 in 2006 (mean age 55.6 years); both genders were equally represented. Patients already treated when they came at the consultation received a mean number of 2.24 antihypertensive drug classes in 2001 and 2.44 in 2006 (p = 0.002). The prescription of three antihypertensive drug classes increased between 2001 and 2006: Calcium channel blockers from 49 % of treated patients in 2001 to 56 % in 2006 (p = 0.007), angiotensin receptor antagonists from 28 to 42 % (p <0.001) and thiazide diuretics from 31 to 39 % (p = 0.001). Thiazide diuretics were included in 48 % of the antihypertensive combinations in 2001 and 55 % in 2006 (p = 0.02). The prescription of ACEI in patients at high cardiovascular risk remained stable around 31 %. CONCLUSION: Antihypertensive treatments were more intensive in 2006 than 2001, but thiazide diuretics remained underused in drug combinations. The prescription of ACEI did not increase in patients at high cardiovascular risk despite convincing evidence of their benefit.

Inheritance of arterial lesions in renal fibromuscular dysplasia.

We have previously shown that patients with renal fibromuscular dysplasia (FMD) have asymptomatic carotid lesions and that familial forms may occur. The objective of this study was to test whether carotid lesions could be detected in relatives of familial cases. High-resolution echotracking of the carotid artery was performed in 47 relatives of 13 cases from six families. This non-invasive investigation led to a semiquantitative arterial score that was compared with that obtained for 47 controls matched for age and sex and that for 125 sporadic cases. Familial resemblance was tested by using a generalized estimating equation approach taking into account the clustering of scores in families. As expected, FMD cases had a significantly higher score than controls (4.02 vs 2.52, P<10(-5)). Familial cases were not significantly different from sporadic cases. Of interest, the 47 apparently healthy relatives of familial cases had also a high carotid score (4.17), very significantly higher than that of controls (2.52, P<10(-5)) even though lower than the corresponding index FMD cases (4.81, P=0.01). Segregation analysis showed that 52% of the descendants of subjects with a score >4 had a score >4, a proportion consistent with autosomal-dominant transmission of the trait. Altogether these results strengthen the hypothesis of renal FMD being a systemic arterial disease and argue for a familial resemblance that may be due to a major genetic effect. The carotid score obtained by high-resolution echotracking may provide a non-invasive surrogate marker for renal FMD of potential value for use in linkage strategies on large pedigrees.

[Pheochromocytoma and pregnancy. Case report]. / Phéochromocytome et grossesse. A propos d'un cas.

The management of a pheochromocytoma during pregnancy is uncommon and is at high risk for both mother and foetus. We report a case of a patient whose first pregnancy was complicated by foetal demise in a context suggestive of preeclampsia. She was diagnosed with pheochromocytoma as she was beginning a second pregnancy. A laparoscopic adrenalectomy was performed in the first trimester of pregnancy, and maternal and neonatal outcome were favourable. This case illustrates the difficulty of diagnosing pheochromocytoma in pregnancy, and the benefits of laparoscopic treatment in the first trimester.

High levels of tyrosine phosphorylated proto-ret in sporadic phenochromocytomas.

Pheochromocytomas are tumors originating from chromaffin cells, the large majority of which are sporadic neoplasms. The genetic and molecular events determining their tumorigenesis continue to remain unknown. On the other hand, RET germ-line mutations cause the inheritance of familial tumors in multiple endocrine neoplasia (MEN)-2 diseases, which account for a minority of pheochromocytomas. We investigated the expression of the RET gene in 14 sporadic tumors harboring no activating mutations. A subset of highly RET-expressing tumors (50%) could be distinguished. They showed RET transcript, protein amounts as well as Ret-associated phosphotyrosine levels similar to those measured in MEN-2A-associated pheochromocytomas. We also determined the GDNF and GDNF family receptor alpha (GFRalpha)-1 transcript levels in tumors and in normal tissues. Whereas the GFRalpha-1 transcripts were detected at similar levels in normal tissues and in tumors, GDNF was frequently found expressed in sporadic tumors at levels several times higher than in controls. These results led us to propose the existence of an autocrine or paracrine loop leading to chronic stimulation of the Ret signaling pathway, which could participate in the pathogenesis of a number of sporadic pheochromocytomas.

Molecular markers and long-term recurrences in a large cohort of patients with sporadic adrenocortical tumors.

Genetic alterations, such as loss of heterozygosity (LOH) at the 17p13 and 11p15 loci and overexpression of the insulin-like growth factor (IGF)-II gene, are associated with the malignant phenotype in sporadic adrenocortical tumors. A high risk of recurrence after surgery for adrenocortical tumors is predicted in cases with regional invasion or distant metastases. However, patients with localized tumors also have a high risk of recurrence. Reliable prognostic markers are required to identify subjects at high risk of recurrence. The aim of this study was to assess the prognostic value of three molecular markers (17p13 LOH, 11p15 LOH, and overexpression of the IGF-II gene) by assessing disease-free survival in a large series of adult patients with sporadic adrenocortical tumors. Adult patients (114) were prospectively followed up from diagnosis of the disease to June 1999 or to death. Malignancy was initially diagnosed in 18 patients (McFarlane stage III: n = 1 and stage IV: n = 17). The remaining 96 patients with localized adrenal disease at diagnosis (stage I: n = 60 and stage II: n = 36) were at risk of recurrence. Histological grade was assessed according to Weiss criteria, and tumors were classified into two groups (Weiss score or=4). Tumor samples were analyzed for LOH at the 17p13 and 11p15 loci and for IGF-II gene mRNA content. 17p13 LOH was a strong predictor of shorter disease-free survival in univariate analysis (P = 0.001; relative risk, 27), as were histological grade (Weiss score >or=4; P = 0.00001; relative risk, 15), 11p15 LOH (P = 0.004; relative risk, 9), tumor size (size >5 cm; P = 0.006; relative risk, 18), and overexpression of the IGF-II gene (P = 0.01; relative risk, 5). In a Cox proportional hazards regression model, histological grade (P = 0.04; relative risk, 4.2) and 17p13 LOH (P = 0.009; relative risk, 21.5) were independently associated with recurrence. Molecular markers, particularly 17p13 LOH, are predictive of long-term outcome in patients with sporadic adrenocortical tumors. In patients who have undergone curative surgery, routine assessment of these tumor markers is a useful complement to histological scoring for predicting recurrence and guiding decisions for subsequent follow-up and management.

European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Standard treatment is surgical resection. Following complete resection of the primary tumour, patients with PPGL are at risk of developing new tumoural events. The present guideline aims to propose standardised clinical care of long-term follow-up in patients operated on for a PPGL. The guideline has been developed by The European Society of Endocrinology and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles. We performed a systematic review of the literature and analysed the European Network for the Study of Adrenal Tumours (ENS@T) database. The risk of new events persisted in the long term and was higher for patients with genetic or syndromic diseases. Follow-up in the published cohorts and in the ENS@T database was neither standardised nor exhaustive, resulting in a risk of follow-up bias and in low statistical power beyond 10 years after complete surgery. To inform patients and care providers in this context of low-quality evidence, the Guideline Working Group therefore prepared recommendations on the basis of expert consensus. Key recommendations are the following: we recommend that all patients with PPGL be considered for genetic testing; we recommend assaying plasma or urinary metanephrines every year to screen for local or metastatic recurrences or new tumours; and we suggest follow-up for at least 10 years in all patients operated on for a PPGL. High-risk patients (young patients and those with a genetic disease, a large tumour and/or a paraganglioma) should be offered lifelong annual follow-up.

Effects of captopril and minoxidil on left ventricular hypertrophy in resistant hypertensive patients: a 6 month double-blind comparison.

In a double-blind 6 month trial, the cardiac effects of captopril and minoxidil, administered as third step treatments, were compared in 34 men with essential hypertension and diastolic blood pressure greater than 95 mm Hg who were taking 200 mg/day of metoprolol and 80 mg/day of furosemide. Average daily doses of captopril and minoxidil were 269 mg (range 150 to 300) and 20 mg (range 7.5 to 30), respectively. At the end of the 6 months' treatment, blood pressure had dropped significantly in both groups, but echocardiographic criteria of hypertrophy improved only in the captopril group (intragroup comparison): blood pressure, thickness of the intraventricular septum and posterior wall, and the left ventricular mass index, respectively, decreased from 163/102 to 135/89 mm Hg (p less than 0.001), 17.4 to 15.9 mm (p less than 0.05), 14.5 to 13.4 mm (p less than 0.05) and 236 to 198 g/m2 (p less than 0.001). In the minoxidil group, blood pressure dropped from 160/99 to 137/87 mm Hg (p less than 0.001), but echocardiographic criteria were not significantly modified. Fractional shortening remained normal in both groups. These results show that in patients with severe left ventricular hypertrophy, captopril-based triple therapy reduces left ventricular mass without altering systolic performance, whereas minoxidil-based therapy does not.

Crossover design to test antihypertensive drugs with self-recorded blood pressure.

In a double-blind, within-patient study, blood pressure was measured at regular intervals at the clinic by the physician and each day at home by the patient. Both methods of blood pressure measurement demonstrated an antihypertensive effect of the diuretics chlorthalidone (25 mg) and triamterene (50 mg) and the beta-blocker oxprenolol (160 mg) and the greater efficacy of the combination of the two therapies. During placebo, as well as during active treatment, blood pressure values were higher at the clinic than at home, except when the patients were taking the beta-blocker, which minimized the arousal response during blood pressure measurements in the clinic. With 2-week treatment periods, separated by 2 weeks of placebo administration, blood pressure returned toward its initial level after each of the three treatments and none of the carryover effects was significant at the 5% level. This methodology was intended to make it possible to demonstrate in 27 patients at the clinic and in 20 patients with measurements made at home, at the usual statistical risks (alpha = 5%, beta = 10%), a fall of 5 mm Hg in diastolic blood pressure in comparison with a placebo. Moreover, at the end of this 3-month follow-up, each patient could continue to receive the treatment that was the most effective and the best tolerated. In conclusion, the use of a within-patient trial design, with a 15-day washout period between active treatments and careful recording of blood pressure values, can minimize the number of patients included in hypertension trials and offer to each patient the possibility of individualization of treatment.

Somatic mutations of the angiotensin II (AT1) receptor gene are not present in aldosterone-producing adenoma.

Angiotensin II stimulates aldosterone secretion from the adrenal zona glomerulosa and mediates most of its biological effects via G protein-coupled type 1 angiotensin II receptors (AT1). A number of G protein-coupled receptors are constitutively activated as a result of somatic mutations in the gene encoding the protein. It is, therefore, possible that primary hyperaldosteronism caused by an aldosterone-producing adenoma (APA) may be the result of constitutive activation of the AT1 receptor. The 1.1-kilobase coding region (exon 5) of the AT1 receptor gene was analyzed in APA and normal adrenal tissue for the presence of mutations using single stranded conformational polymorphism and sequencing techniques. In 17 APAs, no functional mutations were found that could account for the observed pathophysiology. However, three silent polymorphisms were detected in regions encoding the second extracellular loop, the intracellular arm preceding the COOH terminal, and the 3'-untranslated region. In conclusion, somatic mutations in the coding region of the AT1 receptor gene do not appear to play a role in primary hyperaldosteronism caused by an APA.

How much can blood pressure be lowered?

Whatever the therapeutic goal proposed for diastolic blood pressure in hypertensive patients, the actual results of treatment in various health care delivery systems throughout the world are not as good as generally assumed. In the two recent controlled therapeutic trials, 24.5% (Australian trial) and 29.9% (Hypertension Detection and Follow-up Program) of actively treated patients had diastolic blood pressure levels above 90 mm Hg. In three British hospital clinics, diastolic blood pressure was greater than 90 mm Hg in 69% of the treated patients after 6 months to 1 year of treatment. In our own clinic, the blood pressure of 947 hypertensive patients registered in the Artemis system (Paris) between 1976 to 1980 decreased after 2 years on medical treatment from 177/108 to 142/87 mm Hg. However 21.1% of the patients studied still had a diastolic blood pressure above 95 mm Hg. In the general population, the percentage of treated patients not attaining goal levels varies from 42.9% to 71%. Not only is it important to agree upon goals, but it is urgent to standardize methods for collecting and analyzing the results of antihypertensive treatments in various health care delivery systems, since high rates of therapeutic failures might be related to the physician's strategy, the patient's characteristics, the disease's particularities, and the limited efficacy and side-effects of presently available drugs.

Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis: a randomized trial. Essai Multicentrique Medicaments vs Angioplastie (EMMA) Study Group.

Data for the effects on blood pressure of renal artery balloon angioplasty are mostly from uncontrolled studies. The aim of this study was to document the efficacy and safety of angioplasty for lowering blood pressure in patients with atherosclerotic renal artery stenosis. Patients were randomly assigned antihypertensive drug treatment (control group, n = 26) or angioplasty (n = 23). Twenty-four-hour ambulatory blood pressure, the primary end point, was measured at baseline and at termination. Termination took place 6 months after randomization or earlier in patients who developed refractory hypertension. In those allocated angioplasty, antihypertensive treatment was discontinued after the procedure but was subsequently resumed if hypertension persisted. Secondary end points were the treatment score and the incidence of complications. Two patients in the control group and 6 in the angioplasty group suffered procedural complications (relative risk, 3.4; 95% confidence interval, 0.8 to 15.1). Early termination was required for refractory hypertension in 7 patients in the control group. Antihypertensive treatment was resumed in 17 patients in the angioplasty group. Mean ambulatory blood pressure at termination did not differ between control (141+/-15/84+/-11 mm Hg) and angioplasty (140+/-15/81+/-9 mm Hg) groups. Angioplasty reduced by 60% the probability of having a treatment score of 2 or more at termination (relative risk, 0.4; 95% confidence interval, 0.2 to 0.7). There was 1 case of dissection with segmental renal infarction and 3 of restenosis in the angioplasty group. No patient suffered renal artery thrombosis. In unilateral atherosclerotic renal artery stenosis, angioplasty is a drug-sparing procedure that involves some morbidity. Previous uncontrolled and unblinded assessments of angioplasty overestimated its potential for lowering blood pressure.

Glucagon receptor gene mutation (Gly40Ser) in human essential hypertension: the PEGASE study.

A missense mutation (Gly40Ser) in exon 2 of the glucagon receptor gene (GCG-R) was shown to reduce ligand affinity and impair cAMP response. We conducted a case-control study with a sample of 741 French hypertensive patients with moderate to severe hypertension and 412 normotensive control subjects, who were genotyped for this biallelic variant by use of hybridization with allele-specific oligonucleotides. The Gly40Ser polymorphism was not significantly associated with hypertension in the whole study population, although the frequency of 40Ser carriers in hypertensive subjects was double that in normotensive subjects (3.1% in hypertensives versus 1.5%; P=0.087). However, the separate analysis of both genders revealed that 40Ser allele carriers were significantly more frequent (P=0. 035) among male patients (17/429; 4.0%) than among normotensive male controls (2/242; 0.8%), whereas no significant difference was observed in female subjects (6/312 in hypertensives and 4/170 in normotensives). Further studies are required to interpret the significance of this association.

Tumor recurrence and hypertension persistence after successful pheochromocytoma operation.

Pheochromocytoma is a catecholamine-secreting tumor and a rare cause of hypertension that is usually curable. However, pheochromocytoma may recur as a benign or malignant tumor, and hypertension may persist after successful surgical intervention. The frequency of and risk indicators for tumor recurrence and hypertension persistence after successful surgical intervention have not been adequately studied. We determined tumoral and blood pressure outcome in 129 patients followed-up from initial pheochromocytoma resection to death or to 1994 (796 patient-years). We assessed several candidate indicators for their predictive value for the risk of tumor recurrence or hypertension persistence. Recurrence was defined as the reappearance of disease after normalization of biochemical tests. Pheochromocytoma caused death or persistent or recurrent disease in 28 patients. Of the 114 with benign tumors at initial operation, pheochromocytoma recurred as a benign or malignant tumor 17 to 194 months after initial operation in 16 cases. Kaplan-Meier estimates of pheochromocytoma-free survival were 92% and 80% at 5 and 10 years, respectively. In the 98 living patients without recurrence, Kaplan-Meier estimates of hypertension-free survival were 74% and 45% at 5 and 10 years. In the Cox model, familial pheochromocytoma and a low ratio of plasma epinephrine to total catecholamines were independently associated with recurrence. Familial hypertension and age were similarly associated with hypertension persistence. After surgery for pheochromocytoma, patients should be followed-up indefinitely, especially those with familial tumors or a low epinephrine secretion. Pheochromocytoma should not unreservedly be considered a surgically remediable cause of hypertension.