Cardiac Complications as Initial Manifestation of Pheochromocytoma: Frequency,Outcome, and Predictors

ObjectiveTo examine the frequency, outcome, and clinical predictors of cardiac complications as the initial manifestation of pheochromocytoma.MethodsThe medical records of all 76 patients with pheochromocytoma or functional paraganglioma treated at Cedars-Sinai Medical Center, Los Angeles, California, from 1995 to 2011 were reviewed. The patients initially presenting with cardiac complications were identified, and their clinical, laboratory, and imaging characteristics were compared with those of the patients presenting with other complaints, especially hypertension and adrenal mass.ResultsOf the 76 patients, 9 (12%) presented with the following: 2 with acute heart failure, 1 with left ventricular thrombus, 3 with myocardial infarction, and 3 with severe arrhythmia. Failure to diagnose pheochromocytoma resulted in unnecessary invasive interventions in 2 patients. Recovery of cardiac function was excellent after resection of the tumor in all patients. In comparison with the 67 patients presenting with other complaints, the 9 with cardiac complications had similar demographics and cardiac risk factors but harbored larger tumors (6.7 ± 0.8 cm versus 4.4 ± 0.3 cm; P = .015) and exhibited higher biochemical marker levels (23.9 ± 9.0-fold versus 11.3 ± 2.4fold; P = .082), longer corrected QT interval (473 ± 8 ms versus 443 ± 6 ms; P = .015), and lower ejection fraction (43% ± 8% versus 66% ± 2%; P = .002).ConclusionIn this study, 12% of patients with pheochromocytoma initially presented with cardiac complications. Patients with large tumors and high levels of biochemical markers were more likely to develop cardiac injury. Our results confirm that the presence of pheochromocytoma should be ruled out in patients with cardiac diseases and features suggesting pheochromocytoma so that unnecessary interventions can be avoided and cardiac recovery can be achieved. (Endocr Pract. 2012;18:483-492)     

Comparison of Pheochromocytomas and Abdominal and Pelvic Paragangliomas with Head and Neck Paragangliomas

ObjectiveTo compare clinical, radiologic, and pathologic characteristics, as well as management and outcomes, in a series of pheochromocytomas, abdominal and pelvic paragangliomas, and pelvic paragangliomas with head and neck paragangliomas.MethodsIn this retrospective study, we reviewed charts of all patients seen at our institution between January 1995 and December 2006. We searched pathology and medical record databases under the terms pheochromocytoma, paraganglioma, head and neck tumors, carotid body tumors, glomus jugulare, and neuroendocrine tumors. We compared clinical, radiologic, and pathologic characteristics, as well as management and outcomes, between patients with pheochromocytoma, abdominal and pelvic paraganglioma, and head and neck paraganglioma.ResultsEighty-six patients were included (46 with head and neck paraganglioma, 23 with pheochromocytoma, and 17 with abdominal or pelvic paraganglioma). Compared with patients with head and neck paraganglioma, patients with pheochromocytoma or abdominal and pelvic paraganglioma were younger (35.7 ± 16 years vs 43 ± 17 years, P = .042) and were more likely to have the classic triad associated with catecholamine hypersecretion of palpitation, excessive sweating, and headache (40% vs 0%, P < .001); hypertension (70% vs 37%, P = .005); and benign tumors (65% vs 43%, P = .03). Patients with head and neck paraganglioma and patients with pheochromocytoma/abdominal and pelvic paraganglioma were not different in female to male ratios (27:19 vs 29:11, respectively, P = .18), tumor size (5.8 ± 2.7 cm vs 5.7 ± 3 cm, respectively; P = .85), or remission rate (43% vs 60%, respectively, P = .13).ConclusionsHead and neck paraganglioma are similar to pheochromocytoma and abdominal and pelvic paraganglioma in size and outcome, but occur at an older age, lack hyperadrenergic manifestations, and are more likely to have local pressure effects and result in persistent disease. (Endocr Pract. 2009;15:194-202)     

Cardiac Abnormalities Associated with Pheochromocytoma and other Adrenal Tumors

ObjectiveTo study the specific cardiac abnormalities associated with pheochromocytoma and to suggest a strategy for evaluating cardiac function in patients with pheochromocytoma.MethodsIn this case-control study, we reviewed pathology records of patients seen at Cedars-Sinai Medical Center between 1997 and 2007; patients with adrenal or extra-adrenal pheochromocytoma and those with nonfunctioning benign or malignant adrenal tumors were identified. Patients with functioning adrenal adenomas that secreted cortisol or aldosterone were excluded. Clinical history, imaging, pathology, biochemical test results, electrocardiographic findings, and echocardiographic findings were compared between patients with pheochromocytoma and patients with nonfunctioning adrenal tumors.ResultsThe charts of 22 patients with pheochromocytoma and 35 patients with nonfunctioning adrenal tumors were included. No perioperative mortality was observed. The average age of patients with pheochromocytoma was similar to that of control patients (51.9 ± 3.9 years vs 60.2 ± 2.5 years, respectively), as was the number of patients with known cardiovascular diseases (2 [9%] in the pheochromocytoma group vs 5 [14%] in the control group). Two patients with pheochromocytoma (9%) exhibited myocardial damage. Abnormal electrocardiographic findings were present in 16 patients with pheochromocytoma (73%) and in 17 control patients (49%) (P = .1). QTc was prolonged in patients with pheochromocytoma compared with control patients (448.3 ± 9.7 ms vs 424.7 ± 4.5 ms, respectively; P = .02) and was correlated with levels of norepinephrine and normetanephrine, but not with levels of epinephrine and metanephrine or tumor size. ST-T abnormalities were present in 11 patients with pheochromocytoma (50%) and in 8 control patients (23%) (P = .04). Echocardiographic findings were normal in most patients with pheochromocytoma; abnormal left ventricular wall motion was documented in 3 patients with long QTc.ConclusionsThe specific electrocardiographic findings in patients with pheochromocytoma are prolonged QTc and ST-T abnormalities. Performing an electrocardiogram in patients with pheochromocytoma would be prudent. Echocardiography would be useful to examine LV wall motion in patients with long QTc. Coronary artery disease should be excluded in patients with significant ST- T changes. (Endocr Pract. 2009;15:10-16)     

心肌酶谱、动态心电图及冠状动脉CT血管造影诊断嗜铬细胞瘤儿茶酚胺性心脏损害价值研究

摘要 目的：探讨心肌酶谱、动态心电图及冠状动脉CT血管造影诊断嗜铬细胞瘤儿茶酚胺性心脏损害的临床价值。方法：收集2013年1月-2020年4月在我院诊断为嗜铬细胞瘤患者114例,其中嗜铬细胞瘤儿茶酚胺性心脏损害的患者27例。所有患者均完善术前常规检查（血常规、胸片、动态心电图）、心肌酶谱、心脏超声、冠状动脉CTA等临床资料,并收集患者一般临床资料,如血压、临床症状等。结果：114例嗜铬细胞瘤患者中,27例患者存在嗜铬细胞瘤儿茶酚胺性心脏损害。嗜铬细胞瘤儿茶酚胺性心脏损害患者一般临床资料与嗜铬细胞瘤无儿茶酚胺性心脏损害的患者差异无统计学意义（P＞0.05）。嗜铬细胞瘤儿茶酚胺性心脏损害以高血压为主要表现,临床症状表现多样,可伴有头痛、心悸、多汗三联征表现。114例患者中,26例患者出现心肌酶谱升高,36例患者存在不同程度的心电图异常、24例患者冠状动脉CTA异常,嗜铬细胞瘤儿茶酚胺性心脏损害患者在心肌酶谱、动态心电图及冠状动脉CTA异常例数与嗜铬细胞瘤无儿茶酚胺性心脏损害患者中差异均有统计学意义（P＜0.05）。114例患者中心肌酶谱或心电图或冠状动脉CTA异常的患者总共56例,其中嗜铬细胞瘤儿茶酚胺性心脏损害患者23例,嗜铬细胞瘤无儿茶酚胺性心脏损害患者有33例,差异有统计学意义（P＜0.05）。嗜铬细胞瘤儿茶酚胺性心脏损害患者中,心律失常最为常见。结论：嗜铬细胞瘤儿茶酚胺性心脏损害患者心肌酶谱、动态心电图及冠状动脉CTA均可存在异常表现,但特异性、敏感性不高,三者同时综合分析可以提高临床诊断。     

Association of Pheochromocytoma and Ganglioneuroma: Unusual Finding in Neurofibromatosis Type 1

ObjectiveTo report a rare case of association of pheochromocytoma and ganglioneuroma in an asymptomatic patient with neurofibromatosis type 1 (NF1) and to discuss the importance of annual biochemical and imaging studies.MethodsWe present the clinical, laboratory, and pathology findings in a 41-year-old woman with NF1 and review the pertinent literature.ResultsA 41-year-old woman with NF1 presented for a routine gynecologic examination, at which time a right adrenal mass (4 by 3 cm) was discovered by abdominal ultrasonography and confirmed by abdominal computed tomographic scans and magnetic resonance imaging. The patient was normotensive and complained only of discrete essential tremors. Biochemical studies showed a serum epinephrine level of 195 pg/mL (normal,<100) and a 24-hour urine epinephrine excretion of 55 μg (normal,<20), findings consistent with pheochromocytoma. Metaiodobenzylguanidine scintigraphy revealed uptake in the right adrenal gland, with no evidence of metastatic lesions. Before surgical treatment, the patient received an α-adrenergic antagonist for 30 days. Laparoscopic excision of the right adrenal gland yielded excellent postoperative results. Surgical pathology revealed a multinodular mass composed of pheochromocytoma and ganglioneuroma. In patients with NF1 (von Recklinghausen’s disease), a tumor consisting of pheochromocytoma and ganglioneuroma is rare and may be more aggressive than pheochromocytoma alone. An asymptomatic catecholamine-producing tumor may cause substantial morbidity and mortality, especially in patients who are undergoing surgical intervention or are under other stressors.ConclusionThe current guidelines for managing patients with NF1 are an annual history and physical examination. Because of the increased prevalence of pheochromocytoma and ganglioneuroma in patients with NF1, and the potential associated adverse effects, we emphasize the importance of periodic clinical evaluation with biochemical testing and imaging studies. (Endocr Pract. 2007;13:647-651)     

Plasma Free Metanephrine and Normetanephrine Levels are Increased in Patients with Chronic Kidney Disease

ObjectivePatients with impaired renal function, particularly those on dialysis, frequently exhibit high blood pressure and hemodynamic instability, which often lead to pheochromocytoma assessment. Our objective was to assess plasma free metanephrine (MN) and normetanephrine (NMN) in chronic kidney disease patients (CKD) with or without dialysis.MethodsIn this prospective observational study we performed enzyme-linked immunosorbent assays (ELISAs) to evaluate plasma free MN and NMN in 48 CKD patients (15 with stage 3-5 CKD without dialysis, 26 on hemodialysis [HD], and 7 continuous ambulatory peritoneal dialysis [CAPD]), 30 patients with histologically proven pheochromocytoma, and 43 hypertensive patients. Adrenal masses were ruled out by abdominal computed tomography (CT) scans in all CKD and control hypertensive patients.ResultsAll 3 CKD groups (HD, CAPD, and CKD without dialysis) had significantly higher plasma free MN and NMN levels than the control hypertensive group (P < .0055). HD and CAPD patients had significantly lower plasma free NMN (P < .0055), but free MN levels were not significantly different than those observed in pheochromocytoma patients. In patients with HD, CAPD, and CKD without dialysis, plasma free MN and NMN were higher than manufacturer’s upper limits of normal in 57.7% and 28.5%, 13.3% and 61.5%, and 85.7% and 26.6%, respectively. Regression models showed that the number of dialysis years was significantly correlated with plasma free MN (r = 0.615, P < .001) but not free NMN.ConclusionPlasma free MN and NMN levels are frequently elevated in CKD patients, particularly in those on dialysis. Plasma free MN levels significantly overlap with the range in pheochromocytoma patients and correlate with the number of years on dialysis. (Endocr Pract. 2014;20:139-144)     

Clinical Profile of Nonalcoholic Fatty Liver Disease Among Young Patients With Type 1 Diabetes Mellitus Seen at a Diabetes Speciality Center in India

ObjectiveTo estimate the prevalence and clinical profile of nonalcoholic fatty liver disease (NAFLD) among young type 1 diabetes mellitus (T1DM) patients at a tertiary care diabetes center in India.MethodsElectronic medical records of T1DM patients (age at first diagnosis of T1DM ≤ 25 years) registered between January 1992 and May 2013 who had undergone ultrasonography and denied history of any alcohol intake (n = 736) were reviewed. NAFLD was diagnosed if there was any degree of fatty liver. Retinopathy was initially assessed by direct and indirect ophthalmoscopy and later by retinal photography. Nephropathy was diagnosed if urine protein excretion was > 500 mg/day, and neuropathy was diagnosed if a patient’s vibration perception threshold on biothesiometry was ≥ 20 V.ResultsA total of 204/736 (27.7%) T1DM patients had NAFLD. Compared to T1DM subjects without NAFLD those with NAFLD had higher body mass index (BMI) (18.9 ± 4.2 vs. 20.2 ± 4.7 kg/m², P < .001), waist circumference (67.9 ± 13.2 vs. 71.9 ± 13.3 cm, P < .05), systolic blood pressure (110 ± 15 vs. 116 ± 18 mm Hg, P < .001) and diastolic blood pressure (72 ± 9 vs. 74 ± 10 mm Hg, P < .05), while fasting blood glucose (201 ± 101 vs. 183 ± 101 mg/dL, P < .05) and alkaline phosphatase (419 [12.5] vs. 315 [15.8], P < .001) levels were lower in patients with T1DM with NAFLD. Multiple logistic regression analysis showed a significant association between NAFLD and retinopathy (odds ratio [OR]: 2.01, 95% confidence interval [CI]: 1.13-3.43; P = .017, after adjusting for sex, duration of diabetes, overweight/obesity, hypertension, fasting plasma glucose, nephropathy, and nephropathy (OR: 1.89, 95% CI: 1.02-3.50; P = .042), after adjusting for sex and fasting plasma glucose.ConclusionsThis study suggests that NAFLD is also seen among T1DM patients and that it has an independent and significant association with retinopathy and nephropathy. (Endocr Pract. 2014;20:1249-1257)     

Differences in Clinical Manifestations and Tumor Features Between Metastatic Pheochromocytoma/Paraganglioma Patients With and Without Germline SDHB Mutation

ObjectiveTo compare metastatic pheochromocytoma/paraganglioma (MPP) patients with germline SDHB mutations (SDHB MPP) and without SDHB mutations (non-SDHB MPP) in terms of baseline clinical manifestations, tumor characteristics, and outcomes.MethodsClinical data were retrospectively reviewed in 101 MPP patients, including 34 SDHB MPP patients and 61 non-SDHB MPP patients.ResultsSDHB MPP patients presented at a younger age at onset, diagnosis, or metastasis (25 ± 16 vs 36 ± 14, 28 ± 17 vs 38 ± 15, and 31 ± 17 vs 44 ± 14 years old, respectively, P < .01 for all) than non-SDHB patients. Compared with their non-SDHB counterparts, SDHB patients were more likely to have paragangliomas (83% vs 47%, P < .05), synchronous metastases (44% vs 23%, P < .05), bone metastases (80% vs 48%, P < .01), and a shorter progression-free survival (3 years vs 5 years, P < .01). The Ki-67 index was higher in SDHB tumors (P < .05). The 5- and 10-year survival rates were 79% and 74%, respectively, in all patients. Seventeen patients died from MPP, and the time from metastasis to death in patients who had received systemic therapy was significantly longer than in those who had not (3.1 ± 1.5 vs 1.4 ± 0.7 years, P < .01).ConclusionCompared with MPP patients without SDHB mutations, MPP patients with SDHB mutations were younger at onset, diagnosis, or metastasis; had a higher incidence of synchronous metastases, higher ratio of paraganglioma, and higher Ki-67 index; had a shorter postoperative progression-free survival; and were more likely to develop bone metastasis or sole liver metastasis. Our results suggest that patients with SDHB mutations should be identified early and monitored regularly to achieve optimal clinical outcomes.     

Serum Matrix Metalloproteinase-9 Levels in the Diagnosis of Functioning Adrena Tumors

ObjectiveTo investigate whether serum matrix metalloproteinase-9 (MMP-9) levels can be used as a diagnostic tool in determining the functioning status of benign adrenal tumors.MethodsIn this case-control study, medical records of patients with adrenal tumors who consecutively presented to an endocrinology clinic between August 2005 and October 2008 were evaluated. Operation was recommended when the incidentaloma was larger than 4 cm or when a hypersecreting tumor was suspected. A control group of healthy persons matched for age, body mass index, and sex was also enrolled. Patients underwent routine endocrinologic examinations. MMP-9 levels were compared preoperatively and postoperatively. Findings were compared among patients with functioning adrenal tumors, patients with nonfunctioning adrenal tumors, and control participants.ResultsOf 370 patients with adrenal tumors, 50 with adrenal incidentaloma met the inclusion criteria. Twenty- five healthy individuals were enrolled as controls. Group 1 included 20 patients with functioning adrenal tumors (14 with Cushing syndrome and 6 with pheochromocytoma), and Group 2 included 30 patients with nonfunctioning adrenal tumors. MMP-9 levels were higher in patients with nonfunctioning adrenal tumors and functioning adrenal tumors than in control participants (P < .001). MMP-9 levels in patients with functioning adrenal tumors were significantly higher than those in patients with nonfunctioning adrenal tumors (P = .002). After operation, levels decreased significantly in patients with Cushing syndrome and in those with pheochromocytoma; however, patients with Cushing syndrome and pheochromocytoma had similar MMP-9 levels preoperatively and postoperatively. No significant linear correlation existed between tumor volume and MMP-9 levels. A significant positive correlation was determined between preoperative MMP-9 concentrations and 24-hour urinary fractionated metanephrine and epinephrine (r = 0.938, P = .006; r = 0.965, P = .002, respectively), between MMP-9 levels and baseline cortisol levels (r = 0.402, P = .003), and between MMP-9 levels and cortisol levels obtained after dexamethasone suppression testing (r = 0.357, P = .006).ConclusionOur data suggest that serum MMP-9 levels may be useful in differentiating benign subclinical functioning adrenal tumors from benign nonfunctioning adrenal tumors. (Endocr Pract. 2010;16:419-427)     

Urban and Suburban Differences in Hypertension Trends and Self-Care: Three Population-Based Cross-Sectional Studies from 2005-2011

ObjectivesThis study aimed to compare hypertension trends in the urban and suburban population, and to examine the use of several self-care behaviors among patients who were aware of their hypertension.MethodsWe examined the data from three cross-sectional adult populations obtained in 2005, 2008, and 2011, in Beijing.ResultsOur analyses indicated that from 2005 to 2011 the standardized rate of hypertension increased from 31.9% to 36.0% (P <0.001) among urban adults, and was relatively stable (40.8% -40.2%) among suburban adults (P = 0.02). About 10% of the patients reported having taken measures to control their weight for hypertension management. As compared to the other patients, the female patients in the urban areas reported the highest rate of regular BP measurement (52.6%). In addition, the patients who reported taking medication regularly increased among the males and females. Most of the women reported nonsmoking (≥95%) and alcohol abstinence (≥90%). The trend of nonsmoking decreased among the urban males. In contrast, the prevalence of nonsmoking increased among the suburban males, though the trend was not statistically significant (P = 0.055). Further, the patient-reported alcohol abstinence was found to exhibit a decreasing trend among the males.ConclusionsWe observed an increase in the hypertension prevalence from 2005 to 2011. The rates remained higher for suburban adults than for urban adults. Females generally had better self-care ability as compared to male patients. Further research is needed to promote self-care behaviors in hypertensive patients, especially for male patients.     

Comparison of Preoperative Alpha-blockade for Resection of Paraganglioma and Pheochromocytoma

ObjectivePhenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive alpha-blocker) may be equally effective. We compared the efficacy of doxazosin vs phenoxybenzamine.MethodsWe conducted a prospective study of patients undergoing pheochromocytoma or paraganglioma resection by randomizing pretreatment with phenoxybenzamine or doxazosin at a single tertiary referral center. The high cost of phenoxybenzamine led to high crossover to doxazosin. Randomization was halted, and a consecutive historical cohort of phenoxybenzamine patients was included for a case-control study design. The efficacy of alpha-blockade was assessed with preinduction infusion of incremental doses of phenylephrine. The primary outcomes were mortality, cardiovascular complications, and intensive care unit admission. The secondary outcomes were hemodynamic instability index (proportion of operation outside of hemodynamic goals), adequacy of blockade by the phenylephrine titration test, and drug costs.ResultsTwenty-four patients were prospectively enrolled (doxazosin, n = 20; phenoxybenzamine, n = 4), and 15 historical patients treated with phenoxybenzamine were added (total phenoxybenzamine, n = 19). No major cardiovascular complications occurred in either group. The phenylephrine dose-response curves showed less blood pressure rise in the phenoxybenzamine than in the doxazosin group (linear regression coefficient = 0.008 vs 0.018, P = .01), suggesting better alpha-blockade in the phenoxybenzamine group. The median hemodynamic instability index was 14% vs 13% in the phenoxybenzamine and doxazosin groups, respectively (P = .56). The median highest daily cost of phenoxybenzamine was $442.20 compared to $5.06 for doxazosin.ConclusionPhenoxybenzamine may blunt intraoperative hypertension better than doxazosin, but this difference did not translate to fewer cardiovascular complications and is offset by a considerably increased cost.     

Safety and Feasibility of Laparoscopic Resection for Large (≥ 6 CM) Pheochromocytomas Without Suspected Malignancy

ObjectiveTo determine whether laparoscopic adrenalectomy in patients without radiologic evidence of cancer compromises the perioperative and long-term outcomes in patients with large (≥ 6 cm) pheochromocytomas.MethodsWe analyzed a prospective adrenal database of consecutive patients who underwent adrenalectomy at our institution between September 2000 and September 2010. Patients with diagnosed pheochromocytoma who underwent laparoscopic adrenalectomy were included. Patients with tumors smaller than 6 cm were compared with those presenting with tumors 6 cm or larger.ResultsOne hundred fifty-seven patients underwent adrenalectomy, and there were 32 catecholamine-secreting tumors. Of the 33, 7 were excluded from the study because of open surgery. Thus, 25 patients presented with 26 pheochromocytomas and underwent laparoscopic adrenalectomy. Thirteen of the 25 patients (52%) were women. Mean age (± standard error of the mean) was 53 ± 3 years. Mean tumor size was 5.2 ± 0.5 cm, and 11 pheochromocytomas (42%) were 6 cm or larger. Tumor size was significantly different between the large pheochromocytoma and the small pheochromocytoma groups (7.6 ± 0.4 vs 3.6 ± 0.4 cm, P <.001), but there was no significant difference in intraoperative complications, estimated blood loss, cancer diagnosis, or recurrence. The length of stay was comparable between the 2 cohorts, and there were no incidents of capsular invasion or adverse cardiovascular events.ConclusionLaparoscopic adrenalectomy of pheochromocytomas larger than 6 cm is feasible and safe with comparable results to those achieved with laparoscopic adrenalectomy in patients with smaller pheochromocytomas. (Endocr Pract. 2012;18:720-726)     

Nonclassic Presentation of Pheochromocytoma: Difficulties in Diagnosis and Management of the Normotensive Patient

ObjectiveTo report an unusual presentation of pheochromocytoma along with challenges in diagnosis and management.MethodsWe report a clinical case history and describe diagnostic methods and pitfalls. The preoperative medical preparation in a normotensive patient is described.ResultsA 33-year-old man fell off a ladder, resulting in C6 paraplegia. After C7-T1 laminectomy, he was transferred to a rehabilitation center where he reported lightheadedness, shortness of breath, and chest pain during therapy sessions. A left adrenal mass was incidentally discovered during the workup to rule out a pulmonary embolism. He reported no history of hypertension, and no elevated blood pressure readings had been documented. Magnetic resonance imaging of the adrenal glands showed a well-defined left adrenal mass measuring 3.9 × 3.2 × 3.3 cm, which was hyperintense on T2-weighted images. Twenty-four hour urinary catecholamine concentrations were unremarkable; urinary metanephrines were markedly elevated. During hospital admission, blood pressure was in the low to normotensive range, requiring a cautious approach to α-adrenergic blockade and surgical preparation. He underwent uneventful laparoscopic left adrenalectomy; surgical pathology was consistent with pheochromocytoma.ConclusionsThis case illustrates a nonclassic presentation of pheochromocytoma and demonstrates that urinary catecholamines alone are not sufficient for a biochemical diagnosis of large pheochromocytomas. Preoperative preparation in normotensive patients can be achieved with α-adrenergic blockade, hydration, and liberal salt intake.     

Pheochromocytoma in Patients Suspected of Harboring Adrenal Meta stasis: Management and Clinical Predictors

ObjectiveTo study clinical management of patients with suspected adrenal metastasis and to assess whether there are clinical predictors of pheochromocytoma in this patient population.MethodsIn this retrospective cross-sectional study, we reviewed medical records of patients who had adrenalectomy for adrenal lesions or had adrenal biopsy performed between January 1997 and July 2007 in a large academic hospital. Patients who harbored adrenal masses that were suspected of being metastases were identified on clinical findings. Pathologic diagnosis, demographic data, clinical history, imaging studies, and laboratory test results were reviewed and compared among patients whose adrenal mass was determined to be metastasis, adenoma, or pheochromocytoma.ResultsOne-hundred sixty-three patients had adrenalectomy or had adrenal biopsy during the study period. Thirty patients (18%) had adrenal masses that were suspected of being metastases. Of the adrenal masses, 18 (60%) were metastases, 8 (27%) were benign adenomas, and 4 (13%) were pheochromocytomas. Eleven patients (37%) had biochemical testing for pheochromocytoma. Adrenal biopsy was performed without biochemical testing for pheochromocytoma in 9 patients (30%), including 2 subsequently found to have this tumor. Adrenalectomy was performed in 10 patients (33%) without biochemical testing for pheochromocytoma. Clinical parameters were similar among patients with metastasis, adenoma, or pheochromocytoma. There were no clinical predictors to suggest pheochromocytoma.ConclusionsPheochromocytoma occurs frequently in patients suspected of harboring adrenal metastasis, but this tumor is often not considered in clinical practice. The size and imaging characteristics of the adrenal mass and history of known metastasis may help clinicians in decision-making. Biochemical testing for pheochromocytoma should ideally be performed in all patients suspected of having adrenal metastasis. (Endocr Pract. 2008;14:967-972)     

Ordering Pattern and Performance of Biochemical Tests for Diagnosing Pheochromocytoma Between 2000 and 2008

ObjectiveTo examine what tests are ordered by physicians for pheochromocytoma diagnosis and how those tests perform in modern clinical practice.MethodsIn this case series, electronic medical records of patients seen between January 2000 and July 2008 at a large academic hospital in Los Angeles, California, were queried, and patients older than 15 years who underwent any 1 of 5 tests for pheochromocytoma (measurement of plasma catecholamines, plasma fractionated metanephrines, urinary catecholamines, urinary metanephrines, or urinary vanillylmandelic acid) were identified. Because testing was performed in various reference laboratories, test results were classified into 1 of 3 categories: (a) markedly elevated, (b) moderately elevated, or (c) normal. Patient demographics, clinical history, test results, imaging study findings, and pathology records were reviewed.ResultsA total of 3980 tests were ordered for 1898 patients. Pretest probability was 2.2% (based on 681 patients in whom pheochromocytoma was confirmed or excluded), and hypertension was the most common indication for testing. The number of patients tested and the number of tests ordered increased over the years. The ordering pattern stabilized since 2006 when urinary metanephrines, urinary catecholamines, and plasma metanephrines were ordered more frequently. Sensitivity was highest for urinary metanephrines and vanillylmandelic acid, specificity was highest for vanillylmandelic acid and urinary catecholamines, and positive likelihood ratio was highest for vanillylmandelic acid. Positive predictive value for markedly elevated test results was 39% to 83%, while that for moderately elevated test results was only 2% to 14%.ConclusionsOrdering pattern and test performance differ significantly from those recommended and reported by large centers. The best testing strategy should incorporate local experience. Categorizing test results as markedly elevated, moderately elevated, and normal is important for result interpretation. (Endocr Pract. 2009;15:313-321)     

Pheochromocytoma And Pregnancy:A Rare But Dangerous Combination

ObjectiveTo review the literature on pheochromocytoma in pregnancy (PIP) published during the 11-year period 1998 through 2008.MethodsWe searched MEDLINE data sources from 1998 through 2008 using the search terms “pheochromocytoma” and “pregnancy” and reviewed case reports of PIP published in English.ResultsWe identified 54 case reports in MEDLINE data sources, of which 51 reports including 60 cases were reviewed. In comparison with the previous decade, a decreased rate of antenatal diagnosis (from 83% to 70%) and increased maternal and fetal mortality (from 4% to 12% and from 10% to 17%, respectively) were observed. Prematurity was present in 53% of the infants of mothers with antenatally diagnosed pheochromocytoma who gave birth to a live infant. Hypertension was the most common manifestation (88%), with 33% of patients having antepartum hypertensive crises. Urinary catecholamines (64%) and metanephrines (40%) were the most commonly used tests, whereas urinary and plasma metanephrines were the most sensitive tests (100%). Ultrasonography had poor sensitivity (54%), especially during the third trimester. Magnetic resonance imaging was 100% sensitive for adrenal tumors but had only 50% sensitivity for extra-adrenal tumors. A syndromic or familial presentation was seen in 18% of patients, and 32% of patients had bilateral or extraadrenal tumors.ConclusionIn comparison with the previous decade, a decreased rate of antenatal diagnosis and increased maternal and fetal mortality were observed. Prematurity was a major morbidity associated with PIP. Hypertensive crises were more common during pregnancy. Urinary and plasma metanephrines had the highest sensitivity to detect PIP. Genetic screening should be offered to all pregnant women with pheochromocytoma. (Endocr Pract. 2010;16:300-309)     

Osteogenesis imperfecta: the audiological phenotype lacks correlation with the genotype

Background

Neurofibromatosis 1 (NF1), a common autosomal dominant disorder, was shown in one study to be associated with a 15-year decrease in life expectancy. However, data on mortality in NF1 are limited. Our aim was to evaluate mortality in a large retrospective cohort of NF1 patients seen in France between 1980 and 2006.

Methods

Consecutive NF1 patients referred to the National French Referral Center for Neurofibromatoses were included. The standardized mortality ratio (SMR) with its 95% confidence interval (CI) was calculated as the ratio of observed over expected numbers of deaths. We studied factors associated with death and causes of death.

Results

Between 1980 and 2006, 1895 NF1 patients were seen. Median follow-up was 6.8 years (range, 0.4-20.6). Vital status was available for 1226 (65%) patients, of whom 1159 (94.5%) survived and 67 (5.5%) died. Overall mortality was significantly increased in the NF1 cohort (SMR, 2.02; CI, 1.6-2.6; P < 10^-4). The excess mortality occurred among patients aged 10 to 20 years (SMR, 5.2; CI, 2.6-9.3; P < 10^-4) and 20 to 40 years (SMR, 4.1; 2.8-5.8; P < 10^-4). Significant excess mortality was found in both males and females. In the 10-20 year age group, females had a significant increase in mortality compared to males (SMR, 12.6; CI, 5.7-23.9; and SMR, 1.8; CI, 0.2-6.4; respectively). The cause of death was available for 58 (86.6%) patients; malignant nerve sheath tumor was the main cause of death (60%).

Conclusions

We found significantly increased SMRs indicating excess mortality in NF1 patients compared to the general population. The definitive diagnosis of NF1 in all patients is a strength of our study, and the high rate of death related to malignant transformation is consistent with previous work. The retrospective design and hospital-based recruitment are limitations of our study. Mortality was significantly increased in NF1 patients aged 10 to 40 years and tended to be higher in females than in males.     

Acute Myocardial Infarction Attributable to Adrenergic Crises in a Patient with Pheochromocytoma and Neurofibromatosis 1

ObjectiveTo describe a rare case of acute myocardial infarction in a patient with neurofibromatosis 1 and pheochromocytoma and to review the literature on the coexistence of these 2 diseases, the causes of myocardial injury in patients with pheochromocytoma, and the utility of genetic testing and pheochromocytoma screening for those patients and their families.MethodsWe present a case report, including the detailed clinical, laboratory, and radiographic data, results of adrenal mass pathology, and results of coronary angiography. We also survey other relevant reports available in the literature.ResultsA 43-year-old woman with a history of longstanding hypertension, neurofibromatosis 1, headaches, sweating, and palpitations presented to the hospital with chest pain and shortness of breath. She was found to have an acute myocardial infarction and pulmonary edema, as well as a right adrenal mass. A pheochromocytoma was suspected, and phenoxybenzamine was added to her treatment regimen. Cardiac catheterization showed nonobstructive coronary disease. The levels of plasma catecholamine metabolites were extremely high. The patient underwent uncomplicated laparoscopic right adrenalectomy 2 weeks after this admission. Surgical pathology confirmed the diagnosis of pheochromocytoma.ConclusionAdrenergic crisis attributable to pheochromocytoma can result in acute myocardial infarction even in the absence of obstructive coronary disease. Inclusion of pheochromocytoma in the differential diagnosis of hypertension in patients with neurofibromatosis is very important and helps avoid mistakes in the management of such patients. (Endocr Pract. 2007;13:269-273)     

Assessment of Inpatient Fragility Fracture Education and Outpatient Follow-Up at an Urban Tertiary Care Institution

ObjectiveTo assess the impact of inpatient fragility fracture education on follow-up care at an urban tertiary care center with a multidisciplinary inpatient education and follow-up initiative.MethodsParticipants included 139 patients with lowenergy fragility fractures who were identified, educated, and referred for follow-up by a coordinator. Education consisted of an initial 30 to 40-minute session with the patient and family followed by 10-minute sessions on subsequent hospitalization days. Follow-up activities with primary care physicians (PCPs) and orthopaedic surgeons were documented.ResultsOf the 129 patients still living at the end of the study period, 74 (57%) had followed up with their PCP while 93 (72%) had returned to see their orthopaedic surgeons. Women were 2.7 times more likely than men to address the cause of the fragility fracture (95% confidence interval [CI], 1.13-6.97; P = .038) and were 6.18 times more likely to receive treatment or to have bone mineral density (BMD) testing (95% CI, 1.29-29.61; P = .023). Patients previously treated for osteoporosis were 3 times more likely to follow-up with their PCPs (95% CI, 1.10- 8.02; P = .02), while patients who had previous BMD tests were 4.9 times more likely to follow-up (95% CI, 1.89- 12.79; P = .001). We observed a 42% reduction in the likelihood of seeing a physician for osteoporosis evaluation for each additional 10 years of age (95% CI, 13%-61% reduction in odds; P = .008).ConclusionIn the urban setting, follow-up rates are not sufficiently improved by inpatient education. Improved, persistent communication between the orthopaedic surgeon, PCP, and patient is needed to effectively treat patients and prevent future fractures. (Endocr Pract. 2008;14:58-68)     

Cell-free DNA ultra-low-pass whole genome sequencing to distinguish malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion: A cross-sectional study

BackgroundThe leading cause of mortality for patients with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome is the development of malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma. In the setting of NF1, this cancer type frequently arises from within its common and benign precursor, plexiform neurofibroma (PN). Transformation from PN to MPNST is challenging to diagnose due to difficulties in distinguishing cross-sectional imaging results and intralesional heterogeneity resulting in biopsy sampling errors.Methods and findingsThis multi-institutional study from the National Cancer Institute and Washington University in St. Louis used fragment size analysis and ultra-low-pass whole genome sequencing (ULP-WGS) of plasma cell-free DNA (cfDNA) to distinguish between MPNST and PN in patients with NF1. Following in silico enrichment for short cfDNA fragments and copy number analysis to estimate the fraction of plasma cfDNA originating from tumor (tumor fraction), we developed a noninvasive classifier that differentiates MPNST from PN with 86% pretreatment accuracy (91% specificity, 75% sensitivity) and 89% accuracy on serial analysis (91% specificity, 83% sensitivity). Healthy controls without NF1 (participants = 16, plasma samples = 16), PN (participants = 23, plasma samples = 23), and MPNST (participants = 14, plasma samples = 46) cohorts showed significant differences in tumor fraction in plasma (P = 0.001) as well as cfDNA fragment length (P < 0.001) with MPNST samples harboring shorter fragments and being enriched for tumor-derived cfDNA relative to PN and healthy controls. No other covariates were significant on multivariate logistic regression. Mutational analysis demonstrated focal NF1 copy number loss in PN and MPNST patient plasma but not in healthy controls. Greater genomic instability including alterations associated with malignant transformation (focal copy number gains in chromosome arms 1q, 7p, 8q, 9q, and 17q; focal copy number losses in SUZ12, SMARCA2, CDKN2A/B, and chromosome arms 6p and 9p) was more prominently observed in MPNST plasma. Furthermore, the sum of longest tumor diameters (SLD) visualized by cross-sectional imaging correlated significantly with paired tumor fractions in plasma from MPNST patients (r = 0.39, P = 0.024). On serial analysis, tumor fraction levels in plasma dynamically correlated with treatment response to therapy and minimal residual disease (MRD) detection before relapse. Study limitations include a modest MPNST sample size despite accrual from 2 major referral centers for this rare malignancy, and lack of uniform treatment and imaging protocols representing a real-world cohort.ConclusionsTumor fraction levels derived from cfDNA fragment size and copy number alteration analysis of plasma cfDNA using ULP-WGS significantly correlated with MPNST tumor burden, accurately distinguished MPNST from its benign PN precursor, and dynamically correlated with treatment response. In the future, our findings could form the basis for improved early cancer detection and monitoring in high-risk cancer-predisposed populations.

Jeffrey J. Szymanski and colleagues investigate the use of cell-free DNA ultra-low-pass whole genome sequencing to distinguish the malignant peripheral nerve sheath tumor (MPNST) from its benign precursor lesion in patients with Neurofibromatosis type 1 in United States.