Diagnostic and operative problems in multiple pheochromocytomas.

Two children, aged 14 yr, with multiple pheochromocytomas are presented. Both patients had a positive family history. In the preoperative aortographies the intra-adrenal pheochromocytomas of both patients were well visualized, but not the extra-adrenal tumors of the first case. Chlorpromazine as an adrenergic blocking agent was successfully used in the preoperative treatment. Postoperative catecholamine excretion in the first case was repeatedly slightly increased indicating residual pheochromocytoma. In addition to the bilateral adrenal pheochromocytomas, multiple islet cell adrenomas and cholecystolithiasis were revealed at the operation of the second case. After bilateral adrenalectomy and total pancreaticoduodenectomy, regular follow-up examinations were carried out for 28 months. Hyperparathyroidism and signs of possible medullary thryoid carcinoma were discovered. Thus the patient had an unique pattern of MEA syndrome.     

Twenty-five-year surgical experience with pheochromocytoma in children

Our objective was to analyze the presentation, diagnostic localization, operative management, histology, and long-term outcome of a single center's experience with pheochromocytomas in children. A chart review was done to identify all operatively managed pheochromocytomas in patients age 18 years or younger. Open and laparoscopic cases were included. We reviewed the presentation, diagnostic imaging, localization, operative management, pathology, and postoperative outcome of these patients. Clinic visits, contact with the tumor registry, and telephone interviews were used for follow-up. From 1973 through 1999, there were 11 children (four males and seven females) with 14 pheochromocytomas. Two (18.2%) patients had bilateral adrenal lesions and one patient had both adrenal and extra-adrenal tumors. Six (54.5%) patients had extra-adrenal lesions. The average age at operation was 14.7 years (range 9-18 years). Nine (82%) patients had significant hypertension at presentation. CT was used to localize the tumor in eight patients and urine catecholamine levels were used to confirm the diagnosis. Two of the cases were associated with inherited syndromes (multiple endocrine neoplasia 2A and von Hippel-Lindau). Ten patients underwent an open operation and one patient had a laparoscopic resection. The average patient follow-up was 9.2 years (range 9 months to 25 years). There were no operative complications and all patients were alive and well at the time of last follow-up. Three patients (27.2%) had tumors with microscopic malignant features. No tumors recurred or had evidence for metastatic spread. We conclude that peak incidence of pheochromocytomas in children is in early adolescence. Resection can be carried out safely with minimal morbidity and mortality. Current best management of this entity includes establishment of a biochemical diagnosis, adequate preoperative blockade, appropriate imaging, and an individualized operative approach based on tumor location and size.     

Pheochromocytomas: can malignant potential be predicted?

OBJECTIVES: The presence of metastatic lesions is the only acceptable fact to confirm malignant pheochromocytoma. Patients with malignant pheochromocytomas, however, have a very poor survival rate. The aim of our study was to postulate predictive values for malignant pheochromocytomas. METHODS: We evaluated symptoms, diagnostic modalities, treatment, and long-term follow-up of 86 patients with 85 benign and 10 malignant pheochromocytomas. Parameters from the benign were compared with those of the malignant pheochromocytomas. RESULTS: Preoperative 24-hour urinary dopamine was in the normal range for benign pheochromocytomas but increased in malignant pheochromocytomas (P<0.0001). Vanillylmandelic acid was elevated in both benign and malignant pheochromocytomas but higher in malignant than in benign tumors (P = 0.01). No differences could be shown in urinary epinephrine and norepinephrine samplings. Tumor location was divided into 77 adrenal (81%) and 18 extra-adrenal (19%) sites. Malignant pheochromocytomas were located more often at extra-adrenal sites (P = 0.03). There was no increased incidence of malignancy in patients with familial bilateral pheochromocytomas or multiple endocrine neoplasia. Tumors greater than 80 g in weight corresponded to malignancy (P<0.0001). Dopamine tumor concentration was higher in malignant than in benign pheochromocytomas (P = 0.01). Persistent arterial hypertension occurred in 9 (13%) of 72 benign and 6 (60%) of 10 malignant pheochromocytomas (P = 0.001). The 10-year survival rate was 94% for benign pheochromocytomas. All patients with malignant pheochromocytomas died within this period (P = 0.0001). CONCLUSIONS: High preoperative 24-hour urinary dopamine levels, extra-adrenal tumor location, high tumor weight, elevated tumor dopamine concentration, and postoperative persistent arterial hypertension are all factors that increase the likelihood of malignant pheochromocytoma. Patients with these characteristics should have more frequent follow-up evaluations to identify malignancy at earlier states.     

Laparoscopic management of extra-adrenal pheochromocytoma

PURPOSE: Laparoscopic management of extra-adrenal pheochromocytoma presents a unique surgical challenge due to variable anatomical presentation and potential catecholamine surge during operative manipulation. We report our experience with laparoscopic removal of extra-adrenal pheochromocytomas. MATERIALS AND METHODS: Between 1999 and 2002, 5 patients presented with retroperitoneal extra-adrenal pheochromocytomas. Of the patients 2 had a history of von Hippel-Lindau disease, and the remaining 3 patients were diagnosed with sporadic extra-adrenal pheochromocytoma during hypertension evaluation. Although 4 patients had a history of hypertension, only 2 reported symptoms (episodic flushing, headaches, blurred vision) associated with excess catecholamine production. All patients had markedly increased preoperative urinary and plasma normetanephrine and/or norepinephrine levels, and 3 had positive I131 metaiodobenzylguanidine scan. In each case tumor was accurately identified on computerized tomography before surgery. RESULTS: Laparoscopic resection of extra-adrenal pheochromocytoma was successful in 4 patients. Open conversion was required in 1 patient, who also had von Hippel-Lindau related bilateral adrenal pheochromocytomas due to significant adhesion of the extra-adrenal tumor to the aorta and renal hilum, and a concern for possible local invasion. Mean laparoscopic operative time and blood loss were 273 minutes (range 240 to 350) and 119 cc (range 75 to 200), respectively. Three 10 mm ports in a standard triangular fashion were used for the left side tumors, in which the tumors were found lateral to the aorta. For the right side tumors located either in the inter-aortacaval or para-caval region, a fourth port (10 mm) was inserted for liver retraction as needed. Laparoscopic ultrasound was used to localize the tumor and to assess the retroperitoneum for possible metastasis (none detected) in 3 cases. None of the patients had a hypertensive crisis intraoperatively, and all had unremarkable postoperative recovery with an average hospital stay of 3.8 days (range 3 to 4). Plasma and/or urinary norepinephrine and normetanephrine levels returned to normal range postoperatively in all cases. One patient was noted to have left lower extremity lymphedema and gluteal hematoma due to a positional injury related to prolonged pressure from the operating table and was treated conservatively. There has been no tumor recurrence at a median followup of 14 months (range 9 to 36). CONCLUSIONS: With careful surgical planning and appropriate preoperative pharmacological blockade, laparoscopic surgery can be safely performed in patients with extra-adrenal pheochromocytomas with minimal morbidity. Laparoscopic ultrasound may be helpful in precise localization and evaluation of tumor extension.     

Laparoscopic resection of an extra-adrenal pheochromocytoma

Extra-adrenal pheochromocytomas are of rare occurrence. Since first reported laparoscopic adrenalectomy has become the gold standard in the treatment of adrenal tumors, the feasibility of laparoscopic adrenalectomy in the setting of pheochromocytoma has also been established given a careful preoperative planning. Literature on the laparoscopic treatment of extra-adrenal pheochromocytomas is lacking. We report a hypertensive 54-year-old male patient (body mass index, 26.2) with elevated urinary catecholamines and a 6-cm solid mass under the right renal hilum diagnosed after a magnetic resonance. The patient underwent complete transperitoneal laparoscopic excision of the tumor. Recovery was uneventful and final histopathologic examination showed an extra-adrenal pheochromocytoma. We believe that transperitoneal laparoscopic excision of extra-adrenal pheochromocytoma is a feasible and reproducible technique that allows for complete removal of tumoral tissue with low morbidity, shorter hospital stay, and minimal convalescence.     

Extra-adrenal pheochromocytoma.

Extra-adrenal pheochromocytomas may arise in any portion of the paraganglion system, although they most commonly occur below the diaphragm. The most common site of occurrence of extra-adrenal pheochromocytoma is the superior para-aortic region between the diaphragm and lower renal poles. Although the traditional teaching has been that 10% of all pheochromocytomas are at extra-adrenal sites, this may be an underestimation. Extra-adrenal pheochromocytomas probably represent at least 15% of adult and 30% of childhood pheochromocytomas. They may be malignant in up to 40% of the cases, although conflicting data add to the uncertainty of this point. Patients with tumors arising at extra-adrenal sites commonly present with headache, palpitations, sweating and hypertension. The diagnosis is most often confirmed by demonstrating increased catecholamine production, usually by measurement of urinary catecholamines and/or their metabolites. CT scanning is presently the imaging procedure of choice for localization. The roles of MRI and 131I-MIBG scintigraphy in the localization process are still being determined. Thorough preoperative pharmacological preparation, attentive intraoperative monitoring and aggressive surgical therapy all have an important role in achieving the safest and most successful outcome. Complete surgical excision is the treatment of choice for primary extra-adrenal pheochromocytoma as well as recurrent or metastatic disease. When residual tumor cannot be resected, medical therapy for symptomatic relief is preferred, since radiotherapy and chemotherapy have limited effectiveness. Extra-adrenal pheochromocytomas are more likely to recur and to metastasize than their adrenal counterparts, making lifelong followup with annual determinations of catecholamine production essential.     

Limitations of 131I-MIBG scintigraphy in locating pheochromocytomas

131I-metaiodobenzylguanidine (131I-MIBG) scintigraphy for the location of pheochromocytomas has proved to be a major advance in patient management. In combination with computerized tomographic scanning, nearly all pheochromocytomas can be located before surgery and invasive investigations are now indicated only in exceptional cases. However, there are still lessons to be learned concerning the optimal administration and interpretation of 131I-MIBG scintigraphy. With careful attention to detail and an awareness of isotope distribution, false positive studies should be extremely rare. While the incidence of false negative studies is uncommon, these certainly occur. A patient with sporadic bilateral adrenal medullary hyperplasia, bilateral pheochromocytomas, and additional benign pheochromocytomas arising in paraganglia tissue anterior to the abdominal aorta is presented. The right adrenal pheochromocytoma was not identified on 131I-MIBG imaging. We conclude that even with current locating techniques, the traditional surgical approach to pheochromocytoma should not be abandoned. This involves transabdominal exploration of both adrenal glands and careful examination of all possible sites of extra-adrenal pheochromocytomas.     

Transperitoneal, transmesocolic approach for laparoscopic excision of an extra-adrenal pheochromocytoma

Laparoscopic surgery is an established treatment modality for adrenal disease, especially pheochromocytomas. We describe the successful excision of an extra-adrenal pheochromocytoma using a novel transperitoneal, transmesocolic approach. The tumor was located inferior to the left renal hilum in the para-aortic region and was found bulging through the descending mesocolon at laparoscopy. The tumor was removed without mobilization of the descending colon.     

Update on pediatric pheochromocytoma

Pheochromocytomas are rare tumors in children arising from chromaffin cells of adrenal medullary or extra-adrenal paraganglionic tissue. The tumors are characterized by synthesis, metabolism, and secretion of catecholamines. The formerly used guidelines for pheochromocytoma have been changed by recent discoveries, implementation of new approaches, and understanding of biochemistry, genetics, imaging, pathophysiology, and nomenclature of these tumors. In children, pheochromocytomas are more frequently familial, extra-adrenal, bilateral, and multifocal than in adults. Because of a highly variable clinical presentation, pheochromocytoma is often referred to as the great mimic. Measurements of plasma or urinary fractionated metanephrines are recommended as first-line biochemical tests for diagnosis, with optimum diagnostic sensitivity to be preferred over specificity. In general, localization studies must be used secondary to clinical and biochemical evidence. Adequate preoperative treatment with α-blockade is mandatory, including for pheochromocytomas that do not secrete but only synthesize catecholamines. Because approximately 40% of pheochromocytomas in children have a hereditary basis, proper genetic testing should be performed, with appropriate implications for future follow-up and treatment options. The risk for development of malignant disease depends highly on the underlying mutation, which may also impact recommendations concerning screening and surgical or systemic treatment. This article reviews recent advances in biochemistry, genetics, and imaging and outlines recommendations for improved evaluation and treatment of children with benign or malignant pheochromocytomas.     

Functional tumors of the organ of Zuckerkandl.

Chromaffin-reacting pheochromocytomas of the adrenal medulla are the most frequently encountered functional paraganglionic neoplasms. However, extra-adrenal pheochromocytomas as well as non-chromaffin paragangliomas, including those of the carotid body and glomus jugulare, may produce symptoms from catecholamine secretion. One of the extra-adrenal sites from which these tumors arise is from a collection of para-aortic, paraganglion cells around the origin of the inferior mesenteric artery. This collection of paraganglia was described in fetuses by Zuckerkandl in 1901 and has subsequently been referred to as the organ of Zuckerkandl. The diagnosis and management of these neoplasms differ somewhat from that of adrenal pheochromocytomas, but excellent results are often obtained by excision of these lesions. Four patients with functional tumors of the organ of Zuckerkandl are reviewed together with the other reported cases in the literature.     

VMA excretion in patients with pheochromocytoma.

Studies in 20 patients, and a reanalysis of previously published data demonstrate that there is a significant linear relationship between the rate of urinary excretion of 3-methoxy-4-hydroxymandelic acid and the size of a pheochromocytoma. This relationship is most significantly demonstrated in a small group of patients with bilateral adrenal disease as part of the MEN II syndrome. Since not all pheochromocytomas are accurately localized preoperatively and significant numbers can be bilateral or extra-adrenal, this predictive index of tumor size has useful surgical implications. An obvious discrepancy between a prediction of size and operative findings should alert the surgeon to a more thorough search of the opposite adrenal and, indeed, all extra-adrenal paraganglionic sites for other secreting tumor tissue.     

Clipless and sutureless laparoscopic surgery for adrenal and extra-adrenal tumors

BACKGROUND: Newer, energy-based devices like the ultrasonic coagulator (Harmonic Scalpel, Ethicon Endo-Surgery, Inc., Cincinnati, OH) and the LigaSure vessel-sealing system (Valleylab, Boulder, CO) are increasingly being used in advanced laparoscopic procedures. Use of these devices has resulted in shorter operative time, less blood loss, and lower conversion rates. We present our experience with these devices for laparoscopic removal of adrenal and extra-adrenal tumors. METHODS: Ten patients with adrenal tumors and 4 with extra-adrenal tumors were operated on laparoscopically with the ultrasonic shears and LigaSure vessel-sealing system. The entire surgery was carried out using these energy-based devices without using any clips or sutures. RESULTS: No conversions were necessary. None of the patients experienced any major intraoperative or postoperative bleeding. The mean size of the tumor was 6.2 cm (range, 3 to 8). The mean operative time was 123 minutes (range, 80 to 210), and the mean blood loss was 70 mL (range, 10 to 150). Histopathology revealed pheochromocytomas in 7 patients. CONCLUSIONS: Use of the LigaSure vessel-sealing device along with ultrasonic shears for laparoscopic removal of adrenal and extra-adrenal tumors is safe and effective.     

Experience with extra-adrenal pheochromocytoma

From 1955 to 1985, 20 patients presented with a total of 22 extra-adrenal pheochromocytomas (2 had multiple tumors and 2 had a malignant extra-adrenal pheochromocytoma). There were 13 male and 7 female patients, and the highest incidence was in the second decade. Although most patients presented with symptoms typical of pheochromocytoma, several presented with unusual features related to the anatomical location, such as mediastinal mass (chest tumor), upper airway obstruction (neck tumor) or gross hematuria (bladder tumor). In 5 of 6 patients in whom plasma catecholamine levels were fractionated epinephrine levels were elevated. The most common tumor location was the superior para-aortic region (13 patients). In 16 patients the location of tumors was established before treatment. Computerized tomography (9 patients) was the most accurate imaging study for tumor localization. A total of 19 patients underwent complete excision of all pheochromocytomas. Postoperative followup information (median interval 120 months) was available for 15 of these patients. Three patients had recurrent pheochromocytoma that was treated successfully. One patient had essential hypertension. No patient had metastatic disease. The low incidence of malignancy suggests a benign course for extra-adrenal pheochromocytoma and represents a departure from the previously reported higher incidence of malignancy with extra-adrenal pheochromocytoma.     

Laparoscopic resection of periaortic paragangliomas

Paragangliomas are extra-adrenal pheochromocytomas that are often located in the retroperitoneum along the aorta. Although laparoscopic resection is recommended for adrenal pheochromocytomas, few laparoscopic resections for paragangliomas have been reported. We describe the presentation and imaging findings of four patients with periarotic paraganglioma. Laparoscopic resection was successfully performed in three of the four patients; the fourth patient required conversion to an open procedure. This report adds to a growing number of cases documenting that laparoscopic resection of paragangliomas is safe and feasible.     

Pheochromocytoma in children: 15 cases.

Pheochromocytoma is an uncommon tumor in childhood; nevertheless, 20% of all pheochromocytomas are found in the pediatric population. Fifteen children have been treated in our institution from 1962 to 1990. One percent of patients referred over the same period for investigation of high blood pressure were found to have a pheochromocytoma. The majority of patients have hypertension. It varies in intensity and is paroxysmal in about half the patients. Many pediatric cases of unilateral, bilateral, extra-adrenal, familial, and recurrent pheochromocytomas have been reported. We reviewed our 28 years experience with this tumor and concentrated on the diagnosis, the preoperative and operative management, and the occurrence of the multiple endocrine neoplasia syndromes.     

Early identification of patients with von Hippel-Lindau disease at risk for pheochromocytoma

von Hippel-Lindau disease (VHL) is an autosomal dominant familial syndrome that predisposes to the formation of tumors in multiple organ systems, including adrenal and extra-adrenal pheochromocytomas. However, fewer than 30% of VHL families develop pheochromocytomas. In recent years, this clinical heterogeneity has been correlated with missense mutations. The VHL patient requires vigilant, lifelong biochemical and radiographic screening for pheochromocytoma. Half of VHL pheochromocytomas present bilaterally, and there is a high incidence of recurrence after surgery. Because of the morbidity of bilateral total adrenalectomy with subsequent steroid replacement therapy, the recent therapeutic trend has been toward observation and minimally invasive adrenal-sparing procedures.     

Laparoscopic curative resection of pheochromocytomas

PURPOSE: Pheochromocytomas are relatively uncommon tumors whose operative resection has clear medical and technical challenges. While the safety and efficacy of laparoscopic adrenalectomy are relatively well documented, few studies with extended follow-up have been conducted to measure the success of the procedure for the most challenging of the adrenal tumors. In addition, several reports question the applicability of a minimally invasive approach for sizeable pheochromocytomas. The purpose of our investigation was to assess the outcomes of laparoscopic adrenalectomy for pheochromocytomas in the largest study to date when performed by experienced laparoscopic surgeons. METHODS: All pheochromocytomas removed by the authors from January 1995 to October 2004 were reviewed under an Institutional Review Board approved protocol. Eighty-five percent were documented in a prospective fashion. RESULTS: Eighty consecutive patients underwent laparoscopic resection of 81 pheochromocytomas. Seventy-nine were found in the adrenal (42 left, 35 right, 1 bilateral); 2 were extra-adrenal paragangliomas. Eight patients had multiple endocrine neoplasia syndrome. Two lesions were malignant. There were 48 females and 32 males with a mean age of 45 years (range, 15-79 years). Mean tumor size was 5.0 cm (range, 2-12.1 cm); 41 of these lesions were 5 cm in size or larger. Average operative time and blood loss were 169 minutes (range, 69-375 minutes) and 97 mL (range, 20-500 mL), respectively. Intraoperative hypertension (systolic blood pressure, >170 mm Hg) was reported in 53% of patients and hypotension (systolic blood pressure, <90 mm Hg) in 28% of patients. There were no conversions to open surgery. Mean length of stay was 2.3 days (range, 1-10 days). There were 6 perioperative morbidities (7.5%) and no mortalities. No patient required a blood transfusion. No recurrence of endocrinopathy has been documented at a mean follow-up of 21.4 months. CONCLUSION: Laparoscopic resection of pheochromocytomas, including large lesions, can be accomplished safely by experienced surgeons. A short hospital stay with minimal operative morbidity and eradication of endocrinopathy support the minimally invasive approach for adrenalectomy in the setting of pheochromocytoma.     

Extra-adrenal pheochromocytoma: update of the most controversial features. Apropos of two cases

Pheochromocytomas are uncommon neuroendocrine tumors. They are usually symptomatic and sporadic and are generally located in the adrenal medulla. We present two cases of extra-adrenal nonfunctional pheochromocytomas located in the retroperitoneum. The tumors were apparently benign and sporadic and were not associated with other neoplasms or hereditary diseases. Ultrasonography, computed axial tomography and magnetic resonance imaging were performed before complete excision of the tumors using open abdominal surgery. Several immunohistochemical techniques were performed to reach the definitive diagnosis. After 8 and 14 months of follow-up, there is no evidence of recurrence or other syndromes. As a consequence of these two cases, we performed a review of the literature on the topic, focussing on the most controversial areas.     

Malignant pheochromocytoma. A case report and comments on a rare pathology

Pheochromocytomas and functioning paragangliomas are rare tumors arising from the primitive neural crest, and found in the adrenal medulla or elsewhere within the sympathetic paraganglion axis. Clinical symptoms are related to catecholamine production or less frequently to dopamine or other neuropeptides secretion. Malignant pheochromocytomas are very rare tumors comprising between 5-35%, but this value is uncertain because the usual criteria for malignancy, such as mitotic activity, nuclear pleomorphism, are not suitable to discern benign from malignant pheochromocytomas. A specific diagnosis of malignancy requires evidence of invasion of the adjacent organs and the occurrence of metastases. Personal experience is presented with 92 patients affected by: adrenal pheochromocytomas (51 cases), cervical paragangliomas (32 cases), and extra-adrenal paragangliomas (9 cases). Malignant forms were observed in a 23-year-old young woman affected by malignant pheochromocytoma with lymphatic para-aortic metastases (1.9%), and in 2 patients affected by cervical paragangliomas (1 CBT, 1 VBT) with lymph nodal metastases. Careful follow-up of all patients with measurement of the urinary catecholamine is necessary to detect metachronous neoplasm and later metastases, identified with RMN and 131I-MIBG scintiscan.     

Laparoscopic Partial Adrenalectomy for Bilateral Pheochromocytomas

Background  Patients with hereditary pheochromocytoma are at risk of the development of bilateral disease. Partial adrenalectomy can preserve adrenal function to avoid the morbidity associated with medical adrenal replacement. Here, we report a multimedia case study of synchronous bilateral partial adrenalectomy by the laparoscopic approach. Methods  A 13-year-old patient with von Hippel-Lindau disease was found to have high urinary metanephrines and normetanephrines. Computed tomography showed bilateral adrenal tumors (2.5 cm on the right side and 0.9 cm on the left). MIBG scan showed positive uptake in the right adrenal gland without extra-adrenal uptake. After adequate adrenergic blockade, the patient underwent laparoscopic partial adrenalectomy bilaterally. Results  The left side was approached first with the patient in the right decubitus position. Intraoperative ultrasound was performed to determine the line of tumor excision, which was carefully planned to preserve most of the normal-appearing gland. Both tumors were excised completely with good hemostasis. The main adrenal veins of both sides were precisely preserved. Operative time was 228 minutes. No clinically important hemodynamic fluctuations were noted. Pathologic examination confirmed bilateral entirely excised pheochromocytomas. The patient has not required exogenous corticosteroid replacement at follow-up. Conclusion  Laparoscopic partial adrenalectomy for bilateral pheochromocytomas is safe and technically feasible. It should be considered the treatment of choice for hereditary pheochromocytoma. Electronic supplementary material  to this article is available at .