Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma

Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as(123) I-metaiodobenzylguanidine scintigraphy and 6-[(18) F]fluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.     

Diagnosis and localization of pheochromocytoma

This Hypertension Grand Rounds shows how applying new clinical laboratory techniques helped to diagnose pheochromocytoma in a difficult case. In the setting of long-standing, sustained hypertension, the patient had a hypertensive paroxysm during anesthesia induction for surgery, leading to suspicion of a pheochromocytoma. Conventional testing, including CT scanning and fractionated urinary metanephrine test, was not diagnostic. The patient had another hypertensive paroxysm during subsequent anesthesia induction, requiring intensive care. Consistently elevated plasma levels of free normetanephrine provided the first and only biochemical evidence for a pheochromocytoma in this case. 6-[18F]Fluorodopamine positron emission tomography and 123I-metaiodobenzylguanidine scintigraphy subsequently agreed on the existence of a small left adrenal mass, which when removed surgically proved to be a pheochromocytoma. Postoperatively, plasma levels of normetanephrine normalized, and there were no further hypertensive paroxysms, although the patient remained hypertensive. This case illustrates the superiority of plasma levels of free (unconjugated) metanephrines, compared with other biochemical tests, to detect pheochromocytoma. It also confirms that functional imaging by 6-[18F]fluorodopamine or 123I-metaiodobenzylguanidine scanning can localize pheochromocytoma in difficult cases in which other imaging tests are not diagnostic.     

Childhood familial pheochromocytoma. Conflicting results of localization techniques

Childhood familial pheochromocytoma was investigated in four patients by abdominal computed tomographic scan, [131I]metaiodobenzylguanidine scan, and vena caval catecholamine sampling. Results conflicted with surgical findings. Computed tomographic scan identified all four adrenal tumors but missed two midline tumors in one patient. [131I]metaiodobenzylguanidine scan identified two of three adrenal tumors but also suggested extra-adrenal tumors not confirmed at operation in two of three patients. Vena caval sampling for catecholamines confirmed all adrenal tumors but suggested additional tumors not verified at operation in two of three patients. All patients are asymptomatic and have normal urinary catecholamines 15 to 51 months after operation. Because of the frequency of multiple tumors in familial pheochromocytoma, different diagnostic techniques were employed. False-positive results were more frequent with [131I]metaiodobenzylguanidine and vena caval sampling. Reinterpretation of the [131I]metaiodobenzylguanidine scans at a later date led to less false-positive interpretation, although the false-negative rate remained unchanged. More pediatric experience with [131I]metaiodobenzylguanidine scans and vena caval sampling in familial pheochromocytoma is needed. Confirmation of tumor and its localization rest with meticulous surgical exploration.     

34例原发性心脏肿瘤的诊断及外科治疗

目的:探讨原发性心脏肿瘤的临床特征及外科治疗。方法:本院1997年5月至2010年5月,手术治疗原发性心脏肿瘤34例。其中良性肿瘤28例,恶性肿瘤6例。术前均经彩色超声心动图并结合CT、MRI明确诊断。结果:所有患者均在体外循环下施行肿瘤切除,33例痊愈出院,1例死亡。痊愈患者28例良性肿瘤,随访6个月至10年未见复发。5例心脏恶性肿瘤,随访3个月至6个月,3例术后复发,2例死亡。结论:原发性心脏肿瘤,因随时可能发生栓塞,甚至猝死。由于恶性肿瘤进展较快,应早期手术并结合综合性治疗以改善预后。     

Cervical pheochromocytoma: a rare localization and a difficult diagnosis.

A 45-year-old hypertensive female with insulin-treated diabetes mellitus presented to our clinic with elevated urinary norepinephrine (NE) concentrations and a negative 131-metaiodobenzylguanidine (MIBG) scintigraphy, errouneously limited to the abdomen, for evaluation of a pheochromocytoma (Pheo). Despite antihypertensive medications blood pressure remained highly variable and frequently elevated. Further biochemical testing, including a glucagon provocation test and a clonidine-suppression test, revealed autonomous NE secretion. In order to avoid repeat MIBG-scintigraphy, other non invasive imaging techniques were performed, including real time sonography (7.5 MHz) of the neck which revealed a tumor. Fine needle aspiration of this tumor tissue demonstrated cells compatible with Pheo. Histology and immunohistochemistry of the excised tumor confirmed the diagnosis of Pheo. After surgical removal of the tumor, urinary and plasma NE levels normalized. Without any medication the blood pressure of the patient was now only slightly hypertensive. Only half of the daily insulin dose was needed to maintain the patient euglycemic.     

Sympathetic nerve traffic responses to surgical removal of pheochromocytoma.

Pheochromocytoma is usually characterized by a marked increase in peripheral catecholamine secretion. Whether this is accompanied by an alteration in central sympathetic drive has not been clarified. In 6 patients with adrenal pheochromocytoma (mean+/-SEM age, 49. 3+/-7.2 years), we measured systolic and diastolic blood pressure (photoplethysmographic device), heart rate (ECG), venous plasma catecholamines (high-performance liquid chromatography), and postganglionic muscle sympathetic nerve activity (microneurography) before and 78.3+/-13 days after surgical removal of the tumor. In each experimental session, measurements were performed during (1) a 60-minute resting period to compare several values of sympathetic nerve traffic at similar blood pressures before and after surgery and (2) voluntary end-expiratory apnea, ie, a maneuver inducing sympathetic activation. Tumor removal significantly (P<0.05 at least) reduced plasma catecholamines, blood pressure, and heart rate. In contrast, muscle sympathetic nerve activity was significantly (P<0.01) increased, both when quantified as bursts per minute (from 28.1+/-5.7 to 54.3+/-7.5) and as bursts per 100 heartbeats (from 33. 4+/-5.6 to 65.1+/-6.5). This was also the case when data were evaluated in periods of 2 experimental sessions characterized by similar diastolic blood pressure values. The apnea maneuver induced sympathetic nerve traffic responses that were significantly (P<0.05) greater after surgery than before surgery. These data provide the first direct evidence that in pheochromocytoma central sympathetic outflow is markedly reduced and that this reduction cannot be ascribed to a reflex inhibitory response to elevated blood pressures. It is likely that this sympathoinhibition is rather due to a central depression of sympathetic outflow induced by high circulating catecholamines.     

Increases in plasma ouabainlike immunoreactivity during surgical extirpation of pheochromocytoma.

The ouabainlike factor (OLF) is thought to be an important modulator of salt and water metabolism. Plasma OLF could be derived from the central nervous system and/or the adrenal gland. Since the adrenal medulla is of neural origin, the cytology of pheochromocytoma of adrenomedullary origin resembles that of neuronal cells. Ouabainlike immunoreactivity (OLI) is, in fact, present in the adrenal medulla as shown by immunohistochemistry. The plasma levels of catecholamines and OLI were significantly elevated during surgical extirpation of pheochromocytoma in this case. To clarify the origin of circulating OLI in a patient with pheochromocytoma, the relationship between plasma OLI and catecholamines during adrenalectomy was investigated. Plasma catecholamine levels exceeded the normal reference interval, and plasma OLI was positively correlated with the patient's plasma level of norepinephrine. The peak level during operation was about 10 times higher than the baseline level. Both levels reached a maximum when the tumor was mechanically pressed, and then gradually decreased thereafter. The level of OLI in the tumor was higher than that of the normal adrenal cortex. When OLI in the tumor was characterized by reversed-phase high-performance liquid chromatography, the retention time of OLI corresponded with that of authentic ouabain. These results suggest that the circulating OLI in this patients was derived mainly from the pheochromocytoma of adrenomedullary origin.     

Primary aldosteronism: diagnosis, localization, and treatment.

New diagnostic techniques have enhanced the detection of primary aldosteronism. However, the response of blood pressure after operation in unilateral and bilateral adrenal disease is different. We have compared four localizing techniques--adrenal venography, adrenal isotopic scanning, a modified adrenal venous sampling for steroid measurements, and the anomalous postural decrease in plasma aldosterone concentration--in 51 patients with primary aldosteronism, all of whom had undergone operative confirmation. Adrenalectomy resulted in normal blood pressure in 59%, improvement in 25%, and no change in 16%. Correct localization of the lesion was obtained in 47% by the adrenal isotopic scan, in 66% by adrenal venography, and in 91% by the modified adrenal venous hormone technique despite four false-positives. Of the 26 patients with an anomalous postural decrease in plasma aldosterone, 88% had a unilateral lesion.     

Attempted treatment of inoperable pheochromocytoma with streptozocin.

Currently the only treatment available for inoperable pheochromocytoma is symptomatic and palliative with alpha- and beta- adrenergic blockade. Pheochromocytoma is a tumor of chromaffin tissue derived from the neural crest and closely related to other APUD (amine precursor uptake and decarboxylation) cell tumors, including those of the pancreatic islets. Streptozocin has been used with varying success in some of these tumors and therefore merited a trial in pheochromocytoma. We used streptozocin to treat two patients with inoperable pheochromocytoma; the drug failed to have any effect, either on catecholamine excretion or tumor growth.     

The importance of radiology in the localization of pheochromocytoma

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

Malignant pheochromocytoma. Chromaffin granule transmitters and response to treatment

Chromaffin granule transmitters such as chromogranin A and catecholamines have been used in the diagnosis of pheochromocytoma, but the diagnostic and prognostic value of chromogranin A have not been explored in malignant pheochromocytoma. We evaluated these transmitters in patients with pheochromocytoma (n=27), both benign (n=13) and malignant (n=14). Patients with benign pheochromocytoma were studied before and after surgical excision (n=6), whereas patients with malignant pheochromocytoma were evaluated before and after combination chemotherapy with regular cycles of cyclophosphamide/dacarbazine/vincristine (nonrandomized trial in n=9). During treatment, patient responses to chemotherapy were divided according to anatomic and clinical criteria: responders (n=5) versus nonresponders (n=4). Plasma chromogranin A rose progressively (P<0.0001) from control subjects (48.0+/-3.0 ng/mL) to benign pheochromocytoma (188+/-40.5 ng/mL) to malignant pheochromocytoma (2932+/-960 ng/mL). Parallel changes were seen for plasma norepinephrine (P<0.0001), though plasma epinephrine was actually lower in malignant than benign pheochromocytoma (P=0.0182). In bivariate analyses, chromogranin A, norepinephrine, and epinephrine discriminated between pheochromocytoma and control subjects (all P<0.0001), whereas in a multivariate analyses, norepinephrine was the best discriminator (P:=0.011). Chromogranin A was significantly different in benign versus malignant pheochromocytoma on both bivariate (P=0.0003) and multivariate (P:=0.011) analyses. After excision of benign pheochromocytoma, chromogranin A (P=0.028), norepinephrine (P=0.047), and epinephrine (P=0.037) all fell to values near normal. During chemotherapy of malignant pheochromocytoma (n=9), plasma chromogranin A (P=0.047) and norepinephrine (P=0.02) fell but not epinephrine. In 5 responders to chemotherapy, there were significant declines in chromogranin A (P=0.03) and norepinephrine (P=0.03) but not epinephrine; in 4 nonresponders, none of the transmitters changed. Plasma chromogranin A varied longitudinally with tumor response and relapse. We conclude that plasma chromogranin A is an effective tool in the diagnosis of pheochromocytoma, and markedly elevated chromogranin A may point to malignant pheochromocytoma. During chemotherapy of malignant pheochromocytoma, chromogranin A can be used to gauge tumor response and relapse.     

Medical and surgical therapy for cardiac remodeling.

Ventricular remodeling refers to changes in ventricular geometry, volume, mass, and myocellular structure in response to myocardial injury or alteration in loading conditions. Although initially adaptive as a consequence of the initial damage to the myocardium, progressive ventricular remodeling is ultimately a maladaptive process that is associated with significant cardiovascular morbidity and mortality. Treatment with an aim to halt or reverse remodeling with mainly two classes of medications, angiotensin-converting enzyme inhibitors and beta-adrenergic blockers, has been shown to improve the long-term outcome. The role of pharmacologic and surgical therapy in remodeling is evolving and may have an important impact on the development of new directions of therapy for heart failure, myocardial infarction, and hypertension.     

Contribution of cardiac output to renovascular hypertension in man. Relation to surgical treatment

Although cardiac output was on the average higher (P <0.001) in patients with renal arterial disease (42 patients) than in those with essential hypertension (88 patients), levels varied widely within the 2 groups. To determine the possible role of cardiac output variations in the hypertension associated with renovascular lesions, 2 studies were undertaken: (1) Preoperative hemodynamic indexes were studied in relation to arterial pressure response to surgical treatment of the renovascular lesion (12 patients). After anatomically successful surgery (nephrectomy or arterial repair), blood pressure was substantially reduced in 6 patients, and in 5 of the 6 the reduction was associated with a decrease in peripheral resistance. In the other 6 with persistent postoperative hypertension, hemodynamic changes were mixed. Response to surgery was not related to preoperative levels of cardiac output. (2) Correlations between cardiac output and arterial pressure were examined in hypertensive patients of the same age group, 67 with essential hypertension and 35 with renal arterial disease. Among patients with essential hypertension, arterial pressure correlated significantly only with peripheral resistance (r = 0.596, P < 0.001); in contrast, arterial pressure in patients with renovascular hypertension correlated with both cardiac index and total peripheral resistance (P <0.025 and <0.05, respectively). Along with increased output, patients with renal arterial disease also had increased total peripheral resistance (P < 0.001). Thus, although increased cardiac output is a frequent finding in, and possibly a contributor to, renovascular hypertension, it does not appear to be the major factor responsible for its maintenance.