Biochemical and radiological relationships in patients with pheochromocytoma: lessons from a case control study.

BACKGROUND: An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest. AIM: To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines. METHODOLOGY: We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines ≥4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3. RESULTS: The median (range) tumour size in group 1 and group 2 was 4·8 cm (1·7-22) and 3·0 cm (1·7-5) respectively (P < 0·001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre-contrast attenuation ≥17 Hounsfield Units (HU). CONCLUSIONS: Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU.

Pheochromocytoma: state-of-the-art and future prospects.

This review provides current understanding of the pathophysiology of pheochromocytoma and the wide range of associated clinical manifestations that have led to earlier recognition of the disease. In addition, it reviews optimal screening methods and localization techniques that have enhanced the clinician's ability to make the diagnosis with greater certainty. This article will also discuss alternative antihypertensive regimens and innovative anesthetic and surgical procedures that have made successful management more promising than ever before. Areas requiring further development include additional clinical experience with the measurement of plasma metanephrines that have been shown to have high sensitivity and specificity in the diagnosis of sporadic and familial pheochromocytoma, optimizing cost effectiveness of diagnostic imaging, improving the ability to predict and treat malignant pheochromocytoma, and elucidating not only the surgical approach but, perhaps with rapid advances in molecular genetics, ways of preventing familial pheochromocytoma.

Longitudinal Effect of CPAP on BP in Resistant and Nonresistant Hypertension in a Large Clinic-Based Cohort.

BACKGROUND: Clinic-based effectiveness studies of sleep-disordered breathing (SDB) treatment in reducing BP in resistant hypertension (RHTN) vs non-RHTN are sparse. We hypothesize that CPAP use in SDB reduces BP significantly in RHTN and non-RHTN in a large clinic-based cohort. METHODS: Electronic medical records were reviewed in patients with SDB and comorbid RHTN and non-RHTN for CPAP therapy initiation (baseline) and subsequent visits. We estimated generalizable BP changes from multivariable mixed-effects linear models for systolic BP (SBP), diastolic BP, and mean arterial pressure, adjusting for RHTN status, age, sex, race, BMI, cardiac history, and diabetes and repeated measure correlation. RESULTS: Of 894 patients, 130 (15%) had RHTN at baseline (age, 58 ± 12 years; 52% men; BMI, 36 ± 9 kg/m(2)). Patients with RHTN had significantly higher BP overall (P < .001), most notably for SBP (6.9 mm Hg; 95% CI, 3.84, 9.94). In the year following CPAP initiation, improvements in BP indexes did not generally differ based on RHTN status in which RHTN status was a fixed effect. However, there was a significant decrease in SBP (3.08 mm Hg; 95% CI, 1.79, 4.37), diastolic BP (2.28; 95% CI, 1.56, 3.00), and mean arterial pressure (2.54 mm Hg; 95% CI, 1.73, 3.36) in both groups. CONCLUSIONS: In this clinic-based effectiveness study involving patients closely followed for BP control, a significant reduction of BP measures (strongest for SBP) was observed in response to CPAP which was similar in RHTN and non-RHTN groups thus informing expected clinical CPAP treatment response.

Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience.

Radiological characterization of an adrenal tumor as adenoma may decrease the need for follow-up imaging studies, biopsies, and unnecessary adrenalectomies. We retrospectively reviewed 299 adrenalectomies in 290 patients at Cleveland Clinic Foundation over a recent 5-yr period to assess the value of noncontrast Hounsfield units (HU) in characterizing whether an adrenal mass is adenoma or nonadenoma. The mean (+/- SD) HU value for the adrenocortical adenoma/hyperplasia group was 16.2 +/- 13.6 and significantly lower (P < 0.0001) than primary adrenocortical cancers (36.9 +/- 4.1), metastases (39.2 +/- 15.2), and pheochromocytomas (38.6 +/- 8.2). The sensitivity and specificity for 10- and 20-HU cutoff values to differentiate adenomas/hyperplasias from nonadenomas were 40.5 and 100% and 58.2 and 96.9%, respectively. The size of the adrenal tumor had less value with only 40.7 and 81.3% sensitivity and 94.7 and 61.4% specificity for 2- and 4-cm cutoff values. A combination of less than or equal to 4-cm adrenal mass size and noncontrast computed tomography HU less than or equal to 20 had 42.1% sensitivity and 100% specificity. Our study, the largest with surgical histopathology as the gold standard for diagnosis, supports a noncontrast computed tomography attenuation value of 10 HU as a safe cutoff value to differentiate adrenal adenomas/hyperplasias from nonadenomas.

Pheochromocytoma: an approach to antihypertensive management.

Pheochromocytoma and paragangliomas are rare tumors of chromaffin tissue that secrete catecholamines either intermittently or continuously, producing hypertension with a constellation of symptoms and signs that can be frightening to the patient and that continue to provide perplexing problems for clinicians. With surgical treatment, symptoms will be relieved and hypertension normalized or ameliorated for patients who do not have malignant tumors. Appropriate antihypertensive drugs are used to manage hypertension, to control associated cardiovascular symptoms, and to prepare patients for operation. The question debated most often regarding medical therapy of pheochromocytoma is whether antihypertensive treatment regimens other than nonspecific alpha-blockade are just as effective and safe. Understanding the pathophysiologic mechanisms that sustain the hypertension and the pharmacology of antihypertensive agents allows better selection of antihypertensive therapy.

Pheochromocytoma.

Pheochromocytomas cause the most dramatic, life-threatening crises in all of endocrinology. Pheochromocytoma is an explosive clinical syndrome characterized by severe hypertension associated with cardiac complications, hypotension, or even shock and sudden death. The key to diagnosing pheochromocytoma is to suspect it, then confirm it. The cases reported in this review illustrate how the diagnosis can be easily missed and definitive treatment delayed. An appreciation of the wide range of clinical manifestations, based on clear understanding of the mechanisms of catecholamine action and the pathophysiology of pheochromocytoma, and the availability of simple and accurate diagnostic tests should lead to earlier detection of these tumors. Advances in localization techniques and availability of various treatment modalities have made successful management more promising than ever before.

Pheochromocytoma: current perspectives in the pathogenesis, diagnosis, and management.

Pheochromocytomas (pheo) cause the most dramatic, life-threatening crises in all of endocrinology. A proper screening for pheo must be performed in any patient who has: 1) episodic headaches, tachycardia, and diaphoresis; 2) family history of pheo or multiple endocrine neoplasia; 3) incidental suprarenal mass; 4) paroxysms of tachyarrhythmias or hypertension; 5) adverse cardiovascular responses to anesthetic agents, histamine, phenothiazine, tricyclic antidepressants, etc); and 6) spells occurring during exercise, straining, etc. The key to diagnosing pheo is to suspect it, then to confirm it. Early recognition of its presence is critical to avoiding significant morbidity and mortality. Once suspected, the diagnosis can be confirmed with biochemical testing in virtually all patients. The combination of resting plasma catecholamines > or =2000 pg/mL and urinary metanephrines > or =1.8 mg/24 h has a diagnostic accuracy of 98% in both sporadic and hereditary pheos. When available, measurement of plasma free metanephrines should be performed especially in hereditary pheos. Provocative (glucagon) and suppression tests (clonidine) may be necessary when baseline measurements are inconclusive. CT and MRI are equally sensitive for localization (98% and 100%, respectively), but have lower specificities (70% and 67%). MIBG is 100% specific, but less sensitive (78%). The availability of various medical (selective alpha-1- and beta-adrenergic receptor antagonists, calcium channel blockers) and surgical modalities have made successful management more promising than ever before.

Pheochromocytoma: pitfalls in the biochemical evaluation.

The current work-up of a patient suspected to have a pheochromocytoma starts with the measurement of plasma or urine metanephrines. Notably, up to a quarter of these patients will have a false positive result. When the plasma or urine metanephrines are less than the 4-fold upper limit of normal, clinicians struggle between the fear of missing a potentially fatal condition and ordering costly follow up tests. In many cases, ordering unnecessary imaging studies may only increase the level of patient anxiety. This article will review various physiologic factors, pathologic conditions and medications that may influence the levels of catecholamines and their metabolites yielding false positive or false negative results. Acquiring familiarity with these conditions as well as interfering medications will equip clinicians with better interpretation skills of the biochemical tests.

Resistant hypertension: diagnostic strategies and management.

Blood pressure that remains above target levels despite drug therapy is an increasingly common problem. The evaluation of resistant hypertension includes confirming blood pressure measurements with an automated device that works without the clinician present and with 24-hour ambulatory monitoring; assessing for target-organ damage; and determining if kidney disease is present or if the hypertension is secondary to another condition. The goal of management should be to optimize drug therapy by using different classes of appropriate drugs.

Renal denervation to treat resistant hypertension: Guarded optimism.

Renal sympathetic denervation has shown promise in treating hypertension resistant to drug therapy. This procedure lowers blood pressure via targeted attenuation of renal sympathetic tone, and it has a favorable safety profile. But although there is reason for cautious optimism, we should keep in mind that the mechanisms of hypertension are complex and multifactorial, and further study of this novel therapy and its long-term effects is needed.

Comparison of two preoperative medical management strategies for laparoscopic resection of pheochromocytoma.

OBJECTIVES: To compare the intraoperative and postoperative course of patients undergoing laparoscopic pheochromocytoma resection at 2 institutions (Mayo Clinic and Cleveland Clinic) with differing approaches to preoperative preparation. Patients undergoing adrenalectomy for pheochromocytoma typically undergo a preoperative preparation to normalize their blood pressure and intravascular volume. However, no consensus has been reached regarding the best preoperative preparation regimen. METHODS: A retrospective chart review was performed of 50 Mayo Clinic patients and 37 Cleveland Clinic patients who had undergone laparoscopic pheochromocytoma resection. Mayo Clinic predominantly used the long-lasting nonselective alpha(1,2) antagonist phenoxybenzamine, and Cleveland Clinic predominately used selective alpha(1) blockade. Data regarding the intraoperative hemodynamics and postoperative complications were collected. RESULTS: Almost all patients at Mayo Clinic received phenoxybenzamine (98%). At Cleveland Clinic, the predominant treatment (65%) was selective alpha(1) blockade (doxazosin, terazosin, or prazosin). Intraoperatively, patients at Cleveland Clinic had a greater maximal systolic blood pressure (209 +/- 44 mm Hg versus 187 +/- 30 mm Hg, P = .011) and had received a greater amount of intravenous crystalloid (median 5000, interquartile range 3400-6400, versus median 2977, interquartile range 2000-3139; P <.010) and colloid (median 1000, interquartile range 500-1000, versus median 0, interquartile range 0-0; P <.001). At Mayo Clinic, more patients had received phenylephrine (56.0% versus 27.0%, P = .009). No differences were found in the postoperative surgical outcomes, and the hospital stay was comparable between the 2 groups. CONCLUSIONS: Differences in the preoperative preparation and intraoperative management were associated with differences in intraoperative hemodynamics but not with clinically significant outcomes in patients undergoing laparoscopic adrenalectomy for pheochromocytoma at 2 large tertiary care centers.

Change in adrenal mass size as a predictor of a malignant tumor.

OBJECTIVE: To assess the value of adrenal mass absolute growth, growth rate, and percentage growth rate on serial imaging for distinguishing benign from malignant adrenal masses. METHODS: We retrospectively reviewed the Cleveland Clinic medical record data on 136 adrenalectomies or biopsies in 132 patients with 2 imaging studies performed more than 2 months apart (during 1997 to 2008). RESULTS: There were 111 benign (81.6%) and 25 malignant (18.4%) adrenal masses. With use of receiver operating characteristic curve analysis, all 3 aforementioned growth measures showed similar levels of discrimination for the entire study group as well as for the subgroups with 3 to 12 months of follow-up (n = 75 masses) and noncontrast computed tomography Hounsfield units >10 or not reported (n = 111 masses). After adjustment for other factors, the 3 growth measures remained statistically significant predictors of a malignant tumor. The absolute growth cutoff value of 0.8 cm had the highest sum of sensitivity and specificity of 72% and 81.1%, respectively. We could not identify an adrenal mass growth cutoff value to provide 100% sensitivity or specificity to confirm or exclude the presence of a malignant lesion. In 3 patients with metastatic lesions, no growth or a decrease in mass size during a period of 4 to 36 months was observed. CONCLUSION: In this study, the largest with surgical histopathology findings as the "gold standard" for diagnosis, change in adrenal mass size was a significant predictor of a malignant tumor. Nevertheless, we could not identify an adrenal mass growth cutoff value for reliable confirmation or exclusion of a malignant lesion. Change in adrenal mass size should be used in conjunction with other imaging and clinical characteristics when surgical resection is being considered.

Prospective, randomized comparison of transperitoneal versus retroperitoneal laparoscopic adrenalectomy.

PURPOSE: We report a prospective, randomized comparison of transperitoneal laparoscopic adrenalectomy (TLA) vs retroperitoneal laparoscopic adrenalectomy (RLA) for adrenal lesions with long-term followup. MATERIALS AND METHODS: Between December 1997 and November 1999, 57 consecutive eligible patients with surgical adrenal disease were prospectively randomized to undergo TLA (25) or RLA (32). Study exclusion criteria were patient age greater than 80 years, body mass index greater than 40, bilateral adrenalectomy and significant prior abdominal surgery in the quadrant of interest. Mean followup was 5.96 years in the 2 groups. RESULTS: The groups were matched in regard to patient age (p = 0.84), body mass index (p = 0.43), American Society of Anesthesiologists class (p = 0.81) and laterality (p = 0.12). Median adrenal mass size was 2.7 cm (range 1 to 9) in the TLA group and 2.6 cm (range 0.5 to 6) in the RLA group (p = 0.83). TLA was comparable to RLA in terms of operative time (130 vs 126.5 minutes, p = 0.64), estimated blood loss (p = 0.92), specimen weight (p = 0.81), analgesic requirements (p = 0.25), hospital stay (p = 0.56) and the complication rate (p = 0.58). One case per group was electively converted to open surgery. Pathology data on the intact extracted specimens were similar between the groups. Averaged convalescence was 4.7 weeks in the TLA group and 2.3 weeks in the RLA group (p = 0.02). During a mean followup of 6 years 2 patients in the TLA group had a late complication (port site hernia). Mortality occurred in 5 patients, including 1 with TLA and 4 with RLA, during the 6-year followup. CONCLUSIONS: For most benign adrenal lesions requiring surgery laparoscopic adrenalectomy can be performed safely and effectively by the transperitoneal or the retroperitoneal approach.

Aldosterone and specific aldosterone receptor antagonists in hypertension and cardiovascular disease.

Recent preclinical and clinical studies indicate that aldosterone, independent of angiotensin II and elevated blood pressure, may play a role in health and disease. In addition to its role in fluid and electrolyte balance and circulatory homeostasis, more recent studies have identified aldosterone as a critical mediator of vascular damage. In animal studies, aldosterone is implicated in cardiac and vascular fibrosis, renal disease, and cerebrovascular damage. These lesions are prevented by specific aldosterone receptor blockade. In clinical studies, aldosterone receptor antagonism is associated with decreased hospitalization, symptomatology, and mortality, and improvement of endothelial dysfunction in patients with chronic heart failure. A better understanding of aldosterone's actions in nonepithelial tissues should pave the way to better protection of organs at risk such as the kidneys, heart, and brain.

Laparoscopic bilateral partial adrenalectomy for pheochromocytoma.

INTRODUCTION: To describe the technique of transperitoneal laparoscopic bilateral synchronous partial adrenalectomy in a patient with bilateral adrenal pheochromocytoma. TECHNICAL CONSIDERATIONS: An 81-year-old woman with bilateral adrenal pheochromocytoma underwent bilateral laparoscopic partial adrenalectomy. A three-port transperitoneal approach was used for each side, with an additional port for liver retraction during right partial adrenalectomy. Laparoscopic flexible ultrasonography was invaluable for localizing the adrenal tumor and for precise planning of the line of excision. The right main adrenal vein was preserved. Dissection and enucleation of the adrenal tumor and parenchymal hemostasis was achieved effectively using a harmonic scalpel. The total operative time was 2 and 2.5 hours for the left and right adrenal gland, respectively. No major intraoperative hemodynamic instability was noted. The total blood loss was 150 mL, and the hospital stay was 4 days. Pathologic examination confirmed bilateral adrenal pheochromocytoma. CONCLUSIONS: Laparoscopic partial adrenalectomy for pheochromocytoma is safe and technically feasible. Intraoperative ultrasonography is helpful to accurately plan resection of the tumor. If tumor location permits, the main adrenal vein should be preserved to ensure adequate vascularity for the adrenal remnant.