Tetraploidy

A Review

Pulmonary manifestations of pheochromocytoma are infrequent and are not well documented. A MEDLINE search in the English language revealed no cases of endobronchial involvement from a pheochromocytoma. We report a case of endobronchial metastases in a 37-year-old woman known to have a recurrent extra-adrenal pheochromocytoma. She presented with symptoms of wheezing and a nonproductive cough for 8 months and was being treated for asthma. A flexible bronchoscopy with endobronchial biopsy established the diagnosis. The patient underwent a Nd-YAG laser photoresection (LPR) to ablate the tumor, which was followed by placement of a Wallstent (Pfizer Medical Technology Group; Rutherford, NJ). She remains well 18 months later, having required multiple palliative LPRs. To our knowledge, this is the first reported case of endobronchial pheochromocytoma. The pulmonary manifestations of this rare disease and their management are reviewed. (CHEST 1999; 115:511-521)

Key words: endobronchial metastases; pheochromocytoma; pulmonary paraganglioma

Abbreviations: BI = bronchus intermedius; FB = flexible bronchoscopy; LPR = laser photoresection; [MIBG-I.sup.131] = metiodobenzyl-guanidine-iodine 131; RML = right middle lobe; SCLC = small cell lung carcinoma

Thoracic manifestations of pheochromocytoma are infrequent and are not well documented. We cared for a patient with endobronchial metastasis from an intra-abdominal pheochromocytoma, a finding not reported previously. This prompted a MEDLINE search of the literature from 1965 to the present focusing on a review of the pulmonary manifestations of this rare disease.

CASE

A 37-year-old woman known to have recurrent extra-adrenal pheochromocytomas presented with an 8-month history of persistent dry cough and episodic wheezing. She was empirically treated for asthma for 3 months with little improvement. Her medications included albuterol, triamcinolone and ipratropium inhalers, doxazosin, nifedipine, and amitriptyline. She was a 34-pack-year smoker who had quit 10 years before. Her family history was unremarkable.

Her history was significant for a pheochromocytoma that had been diagnosed at age 8, requiring a right adrenalectomy and nephrectomy, and a splenectomy. Over the next 25 years, local recurrences required multiple surgical excisions. The patient was known to have a solitary pulmonary nodule in the right lung, which was presumed to be a metastatic pheochromocytoma that had been radiographically unchanged for the previous 8 years.

Hormonal assays performed on separate occasions confirmed the diagnosis of pheochromocytoma with results that showed elevated levels of 24-h urinary normetanephrine, and serum epinephrine and chromogranin A (Table 1). Tumor localization using a chest CT scan, an MRI scan of the chest, and a met-iodobenzyl-guanidine-iodine 131 ([MIBG-I.sup.131]) scan also was undertaken (Table 2).

Table 1--Results of Hormonal Assays Used to Diagnose Pheochromocytoma

Table 2--Results of Radiologic Methods Used to Localize Pheochromocytoma

Clinical examination revealed a pulse of 105/min, BP of 150/105 mm Hg, and localized wheezing at the fight lung base. A chest radiograph revealed a fight hilar mass, an enlarged azygous lymph node, and a fight middle lobe (RML) infiltrate (Fig 1). A chest CT scan (Fig 2) confirmed anterior carinal, subcarinal, and right hilar adenopathy and an infiltrate in the RML.

[Figures 1-2 ILLUSTRATION OMITTED]

Outpatient flexible bronchoscopy (FB) revealed (Fig 3) a splayed main carina and an exophytic mass occupying the bronchus intermedius (BI), on which a biopsy was performed. The tumor mass occluded the BI by 80 to 90%. Extrinsic compression prevented passage of the FB into the RML. The endobronchial biopsy was compared with the original tissue specimen obtained at the time of initial presentation and confirmed the diagnosis of pheochromocytoma (Figs 4-6). Archival paraffin-embedded tissue blocks of the original specimen were analyzed for DNA ploidy using the Hedley technique,[1] and the tumor was found, to be diploid. Nd-YAG laser photoresection (LPR) with concomitant placement of a 10 x 20-mm Wallstent (Pfizer Medical Technology Group; Rutherford, NJ) established near total patency of the BI distally with marked symptomatic relief. The patient remains well 18 months later, having required periodic palliative LPR.

[Figures 3-6 ILLUSTRATION OMITTED]

DISCUSSION

While pulmonary involvement with pheochromocytoma is uncommon, endobronchial involvement has never been reported. The following is a literature review of the pulmonary manifestations of this rare disease and its management.

The incidence of pheochromocytoma ranges from 0.3 to 0.95%[2,3] of neuroendocrine tumors, which arise from chromaffin tissues of the sympathetic nervous system. Adrenal tumors are called "pheochromocytomas," and extra-adrenal tumors are called "paragangliomas." These tumors are sporadic or familial and are associated with multiple endocrine neoplasia (2A and 2B) and neuroectodermal syndromes (tuberous sclerosis, neurofibromatosis, Von Hippel-Lindau syndrome, and Sturge-Weber syndrome).[4] Rare associations with Zollinger-Ellison syndrome and Carney's triad of paragangliomas, gastric epithelioid leiomyosarcomas, and pulmonary chondromas are reported.[5,6] Approximately 50% of familial and 10% of sporadic adrenal tumors are bilateral, the latter being more common in younger patients with familial tumors. Malignant pheochromocytomas are rare in the pediatric age group.[7] The salient differences between adrenal and extra-adrenal tumors are summarized in Table 3.[7-14] The common locations of extra-adrenal tumors are listed in Table 4.[7,11,15,16]

Table 3--Differences Between Adrenal and Extra-adrenal Pheochromocytoma[7-14]

(*) F = female; M = male; (+) and (+++) = quantifies the amount of enzyme secreted.

About 90% of pheochromocytomas are located below the diaphragm, with 85 to 95% occurring in the adrenal medulla.[3,17] Intrathoracic lesions occur in 10% of patients and arise in the costovertebral gutter in close association with the sympathetic chain.[16] Other sites include the anus,[16] distal ureter,[18] prostate,[19] sacrococcygeal area,[20] spermatic cord,[21] renal capsule, uterine broad ligament,[22] ovary,[23] and vagina.[24]

Pathology

The tumor varies in size (2 to 3 kg), and is generally encapsulated and vascular. Symptoms bear little relationship to tumor size. Larger tumors have a tendency to become hemorrhagic and necrotic. Microscopically, tumor cells are arranged in clusters or cell nests separated by endothelium lined spaces in a "Zellballen" pattern, which is typical of pheochromocytoma. Cells vary in size and shape, and they have a granular basophilic to eosinophilic cytoplasm, round to oval nuclei, and prominent nucleoli with granular chromatin. Hyperchromasia, while being fairly common, does not correlate with malignancy potential. Immunohistochemical stains for chromogranin are strongly positive. Electron microscopy reveals vesicles filled with norepinephrine and epinephrine.[17]

There are no reliable histologic features that can predict malignancy other than the finding of metastatic disease. Malignancy can be diagnosed with certainty only by demonstration of the existence of tumor cells in sites where chromaffin tissue would not normally occur (lymph nodes, bones, muscle, liver, brain, and lung).[10] The study of chromosomal ploidy in tissue can assist in predicting tumor behavior, with normal DNA histograms predicting a benign course and tetraploidy/polyploidy predicting malignant behavior.[25,26] Cases of diploid metastatic pheochromocytomas have, however, previously been reported.[26] Our patient was found to have an encapsulated, histologically bland, diploid tumor at initial diagnosis, yet later she presented with local recurrence and metastatic disease.

THORACIC MANIFESTATIONS OF PHEOCHROMOCYTOMA

The pulmonary manifestations of pheochromocytoma are listed in Table 5.

This is the most common presentation of primary thoracic pheochromocytoma.[27] In a review of 41 patients with mediastinal paraganglioma, 8 patients died of tumor progression and 4 from metastatic disease; 19 were alive without recurrence 5 months to 21 years after therapy.[28] In a second series, posterior mediastinal paragangliomas were predominant in young men (mean age, 29).[29] Half the patients (15/30) had clinical symptoms related to excess catecholamines, 7 patients had multiple lesions, and 13 were alive and tumor free at an average of 2.2 years postsurgery.

Mediastinal paragangliomas, because of their unusual site, pose problems in diagnosis. Anterior mediastinal tumors are more frequent, larger in size, less amenable to surgery, and occur in older patients.[30] Posterior mediastinal paragangliomas must be differentiated from sarcomas, renal cell carcinomas, and metastatic melanomas. A majority of these tumors are indolent but should be followed up regularly. Surgery is the treatment of choice for well-circumscribed lesions.

Metastatic Pulmonary Disease

Multiple parenchymal nodules are the most common thoracic manifestation of malignant pheochromocytoma. Their clinical characteristics are similar to other malignancies, with hematogenous spread being most common. In general, the lesions are peripheral, multiple, variable in size, and have sharp edges. A cystic appearance can be seen if there is tumor necrosis. While metastases to mediastinal and hilar lymph nodes are well described, lymphangitic, pleural, and endobronchial involvement have not been reported.[31-33] Hemoptysis and positive sputum cytology have been described in a single case with parenchymal

metastases at autopsy.[34] The mean interval from initial diagnosis to the development of extra-adrenal metastases is 9 years.[35]

Pulmonary Edema

This is a well-recognized complication of epinephrine producing pheochromocytomas.[36-43] Proposed mechanisms include diastolic dysfunction from hypertension, a reversible catecholamine cardiomyopathy, focal ischemic myocarditis, acute aortic insufficiency from aortic dissection, and hypertrophic cardiomyopathy with outflow tract obstruction. It also has been suggested that the administration of [Beta]-blockers may cause an unopposed [Alpha]-stimulation, increase afterload, and precipitate pulmonary edema. There has been a case report of pulmonary edema occurring after the administration of an IV contrast material for aortography.[44] The treatment of pulmonary edema associated with pheochromocytoma requires selective [Alpha]- and [Beta]-blockade with concurrent tumor removal. While labetolol has been used previously in this situation, [Alpha]- and [Beta]-blockade are best accomplished using a combination of phenoxybenzamine and metoprolol, respectively.

Noncardiogenic Pulmonary Edema

This manifestation has been noted in case reports of pheochromocytoma with bilateral pulmonary infiltrates, normal pulmonary capillary wedge pressure, and no evidence of infection.[45-47] The infiltrates resolved following surgical resection of the tumor. Its pathogenesis is thought to be similar to neurogenic pulmonary edema and may be due to massive [Alpha]-adrenergic stimulation by sympathetic discharge and increased capillary permeability.[45] Supportive measures and control of the hyperadrenergic state should result in recovery in most cases before surgical intervention is necessary.

Altered Airway Reactivity

There are several case reports of the reappearance of bronchial hyperreactivity following resection of catecholamine-secreting tumors.[48-52] The complex relationship between the autonomic nervous system and airway sensitivity is not fully understood. Bronchomotor tone is controlled by a balance between the sympathetic and parasympathetic nervous systems.[51] It is thought that desensitization of [Beta]-receptors due to chronic catecholamine excess results in decreased [Beta]-stimulation and consequent bronchospasm following surgical removal of the tumor. In addition, preoperative [Beta]-blockade appears to worsen bronchospasm.

Sarcoidosis and Pheochromocytoma

There are isolated reports of an association between sarcoidosis and pheochromocytoma.[53,54] There are no data to support a causal relationship between sarcoidosis and pheochromocytoma based on the independent incidences of the two diseases.

Histopathologic Mimics With Bronchial Carcinoids and Small Cell Carcinoma

The diagnosis of primary pulmonary paraganglioma first requires the exclusion of an extrapulmonary paraganglioma. The existence of paragangliomas as primary tumors of the lung is controversial. It had been suggested that bronchial carcinoids, pheochromocytoma, and small cell lung carcinoma (SCLC) represented an evolutionary continuum among neuroendocrine tumors.[55] Although carcinoid tumors are more common than paragangliomas, considerable overlap exists in the histologic features of these tumors without specific discriminating features found by electron microscopy or immunohistochemistry. Neoplastic cells positive for S-100 protein can be found in both types of tumors. However, up to 80% of carcinoids stain with keratin, while paragangliomas are virtually always keratin negative. The presence of carcinoid syndrome favors a carcinoid tumor.[56] Since both carcinoid tumors and paragangliomas are low-grade malignant tumors with a similar prognosis, there is probably little clinical significance to making the pathologic distinction.

In an isolated case report, a fine-needle aspiration biopsy of the left adrenal gland tumor closely mimicked a SCLC, until it was confirmed to be a pheoehromocytoma on immunohistochemical staining.[57] An adrenal

pheochromocytoma should be included in the differential diagnosis of small round cell neoplasms seen on fine-needle aspirates of the adrenal gland until it is confirmed by immunohistochemistry.[57]

Miscellaneous

Isolated cases of upper airway obstruction from a paraganglioma in the neck and superior mediastinum, aortopulmonary adenopathy,[58] intracaval extension of the tumor,[59,60] recurrent pulmonary emboli, and polycythemia in association with pheochromocytoma have been reported.[60] Catecholamine-triggered anxiety with respiratory alkalosis and lactic acidosis have been described. The pathogenesis of lactic acidosis includes peripheral vasoconstriction and increased tissue lactate production with impaired oxygen delivery and diaphragmatic function.[61-63]

Endobronchial Disease

Clinically significant metastatic disease in major airways from any form of malignancy occurs in [is less than] 5% of cases.[64,65] To our knowledge, no case of pheochromocytoma metastasizing to the bronchus exists in the literature. In our case, the diagnosis of endobronchial disease was easily established by FB. We suggest that the treatment of endobronchial metastases from a pheochromocytoma be approached utilizing the same principles that apply to other endobronchial tumors.[66,67]

DIAGNOSIS

The diagnosis of pheochromocytoma is confirmed by a combination of high clinical suspicion, abnormal screening tests (increased urinary metanephrine and vanillylmandelic acid), and elevated levels of plasma epinephrine/norepinephrine.[68] A serum norepinephrine level of [is greater than] 2,000 pg/mL is diagnostic of pheochromocytoma.[69] In patients with norepinephrine levels of 50 to 2,000 pg/mL, and where the diagnosis of pheochromocytoma is not clear cut, a clonidine suppression test is useful.[70] In patients who are on ganglion-blocking drugs, supine plasma chromogranin A is a useful adjunct in the diagnosis, having a sensitivity of 83% and a specificity of 96%.[7]

Localization of the tumor screens for multicentric and metastatic extra-adrenal disease, allows for a direct operative approach to the tumor and minimizes operation time. Commonly used procedures to locate pheochromocytomas are CT scan, MRI, and MIBG-I[131] scanning,[67,69,71] with each modality having advantages and disadvantages (Table 6).

Table 6--Comparison of Various Imaging Techniques in Pheochromocytoma Diagnosis

Selective venous sampling and arteriography are useful if the results of other imaging techniques are normal or if surgical excision of a large tumor at a difficult location is planned.[81] The diagnostic workup of pheochromocytoma/paraganglioma is detailed in Figure 7.

[Figure 7 ILLUSTRATION OMITTED]

TREATMENT

Surgical resection is the definitive treatment for pheochromocytomas/paragangliomas. The mortality for adrenalectomy currently ranges between 2 and 4%. Good perioperative care is essential to reduce mortality.[70]

Preoperative medical management consists of control of the hypertension and catecholamine excess (as indicated by tachycardia and cardiac arrhythmias) with [Alpha]- and concurrent [Beta]-blockade. Although there is no evidence that preoperative [Alpha]-blockade reduces perioperative mortality,[82] its benefits clearly outweigh its risks. Drugs commonly used are phenoxybenzamine, prazosin, terazosin, and doxazosin, with all being equally effective. Plasma volume expansion should be reserved for patients with significant volume deficits and must be monitored closely in an intensive care unit or the operating room to avoid complications (eg, congestive heart failure).

[Beta]-Blockers are relatively contraindicated in the absence of prior [Alpha]-blockade, as unopposed a-1 vasoconstriction may precipitate a hypertensive crisis, pulmonary edema, and shock.[83] Calcium channel blockers have been used to control blood pressure and prevent catecholamine-induced coronary vasospasm. In refractory cases, a catecholamine receptor blocker, metyrosine, which is a tyrosine hydroxylase inhibitor of the rate-limiting step in catecholamine synthesis, can be used.[84]

Intraoperatively, IV nitroprusside, nitroglycerin, and phentolamine are used for hypertensive control. Tachyarrhythmias can be managed with esmolol, a short-acting [Beta]-blocker. These measures also should be followed during endobronchial excision of the tumor.

Postoperative follow-up includes the measurement of plasma catecholamines at day 7 and annually for 5 years, and blood pressure checks every month for a year and then every 6 months for life.[70] Some researchers advocate annual MIBG-I[131] scans to detect recurrence.[85]

When recurrences or metastases are demonstrated, surgical removal or debulking is the treatment of choice. Overall, the 5-year mortality is approximately 44%.[13,86] If the patient is a poor surgical risk or if the tumor is inoperable, intraarterial embolization, combination chemotherapy, radiotherapy, or MIBG-I[131] therapy can be used with varying degrees of success in conjunction with medical management.[11,87,88]

External beam radiation with 3,000 to 5,000 cGy provides palliation in skeletal deposits but is less successful in soft tissue deposits.[13] Some researchers have reported benefit from radiating the sites of recurrence and lymph node metastases.[86]

Cytotoxic chemotherapy has been found to be associated with tumor shrinkage in 57% of eases and with biochemical response in 80% of cases.[89] The most promising agents are a combination of cyclophosphamide, vincristine, and dacarbazine, with preliminary partial responsive rates of 57% (mean duration, 21 months).[87] Other agents like nitrosurea, streptozocin, and doxorubicin have been used with limited success.[86]

The long-term efficacy of high-dose MIBG-I[131] remains unproven.[83,90-92] A study in France involving 15 patients suggested clinical improvement, with the mean duration of hormonal response being 26 months with a tumor response of 36 months.[90] However, the response to chemotherapy and/or MIBG-I[131] is variable. Figure 8 summarizes the treatment of pulmonary paragangliomas.

[Figure 8 ILLUSTRATION OMITTED]

Lifelong follow-up is mandatory in all patients with pheochromocytoma, as late recurrence or metastasis is known to occur, especially in patients with familial disease.[26] Some advocate yearly MIBG-I[131] scans for early detection of recurrences.[85]

The prognosis of primary pulmonary paraganglioma is good, with reports of prolonged survival of several decades.[93] Patients with pulmonary metastasis have a poor prognosis, with a mean survival of 1 to 2 years.[11,86]

CONCLUSION

Pheochromocytomas, although rare, may arise in extra-adrenal locations in 10% of cases and can be malignant in 40%. Pulmonary metastases have been well described primarily as parenchymal densities or mediastinal masses. Except for our case, endobronchial metastases have never been reported. Localization of the tumor is best with MRI, which has a sensitivity of 100% for extra-adrenal tumors, or a contrast CT scan. MIBG-I[131] scans should be reserved for cases in which clinical suspicion is high despite a negative chest CT scan and for the follow-up patients with recurrent and/or metastatic disease. The definitive cure is surgery for well-localized tumors along with concurrent medical management of catecholamine excess, hypertension, hypovolemia, and hypoglycemia. Recurrent and metastatic disease can be debulked with surgery following detection with an [MIBG-I].sup.131] scan. The roles of chemotherapy, external beam radiation, and MIBG[I.sup.131] therapy are still under investigation.

(*) From the Department of Pulmonary and Critical Care Medicine (Drs. Sandur, Dasgupta, Arroliga, and Mehta) and the Department of Pathology (Dr Shapiro) The Cleveland Clinic Foundation, Cleveland, OH.

Manuscript received March 25, 1998; revision accepted August 12, 1998.

Correspondence to: Atul C. Mehta, MD, FCCP, Department of Pulmonary and Critical Care Medicine, Desk A90, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195 Mediastinal Paragangliomas

REFERENCES

[1] Hedley DW, Friedlander ML, Taylor IW. Application of DNA flow cytometry to paraffin-embedded archival material for the study of aneuploidy and its clinical significance. Cytometry 1985; 6:327-333

[2] Beard CM, Sheps SG, Kurtland LT, et al. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc 1983; 58:802-804

[3] Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma: review of a 50 year old autopsy series. Mayo Clin Proc 1981; 56:354-360

[4] Neuman HPH, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia--type 2, and Von-Hippel--Lindau disease. N Engl J Med 1993; 329:1531-1538

[5] Nishikawa M, Masaki M, Masaki H, et al. Zollinger-Ellison syndrome and pheochromocytoma: report of a case. Horm Metab Res 1993; 25:180-183

[6] Carney JA, Sheps SG, Go VL, et al. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chrondroma. N Engl J Med 1977; 296:1517-1518

[7] Ein SH, Weitzman S, Thorner P, et al. Pediatric malignant pheochromocytoma. J Pediatr Surg 1994; 29:1197-1201

[8] Melicow MM. One hundred cases of pheochromocytoma (107 tumors) at the Columbia-Presbyterian Medical Center 1926-1976: a clinico-pathologic analysis. Cancer 1977; 40: 1987-2004

[9] Whalen RK, Aithausen AF, Daniels GH. Extra-adrenal pheochromocytoma: review article, J Urol 1992; 147:1-10

[10] Goldfarb DA, Novick AC, Bravo EL, et al. Experience with extra-adrenal pheochromocytoma. J Urol 1989; 142:931-936

[11] Remine WH, Chong GC, Van-Heerden JA, et al. Current management of pheochromocytoma. Ann Surg 1974; 179: 740-748

[12] Van-Heerden JA, Shelps SG, Hamberger B, et al. Pheochromocytoma, current status and changing trends. Surgery 1982; 91:367-373

[13] Scott HW Jr, Halter A. Oncological aspects of pheochromocytoma: the importance of follow-up. Surgery 1984; 96:1061-1066

[14] Gibbs MK, Carney JA, Hayles AB, et al. Simultaneous adrenal and cervical pheochromocytoma in childhood. Ann Surg 1977; 185:273-278

[15] Modlin IM, Farndon JR, Shephard A, et al. Pheochromocytomas in 72 patients: clinical and diagnostic features, treatment and long term results. Br J Surg 1979; 66:456-465

[16] Fries JG, Chamberlin JA. Extra-adrenal pheochromocytoma: literature review and report of a cervical pheochromocytoma. Surgery 1968; 63:268-275

[17] Samaan NA, Hickey RC, Shutts PE. Diagnosis, localization and management of pheochromocytoma: pitfalls and follow-up in 41 patients. Cancer 1988; 62:2451-2460

[18] Das S, Bulusu NV, Lowe P. Primary vesical pheochromocytoma. Urology 1983; 21:20-25

[19] Nielsen VM, Storgaard N, Kvist N. Pheochromocytoma of the prostate. Br J Urol 1987; 59:478-479

[20] Waaler E. A chromaffin tumor simulating Grave's disease. Acta Med Scand 1945; 123:1

[21] Eusebi V, Massarelli G. Pheochromocytoma of the spermatic cord: report of a case. J Pathol 1971; 105:283-284

[22] Aron DC, Marks WM, Alper PR, et al. Pheochromocytoma of the broad ligament: localization by computed tomography and ultrasonography. Arch Intern Med 1980; 140:550-552

[23] Fawcett FJ, Kimbell NKB. Pheochromocytoma of the ovary. J Obstet Gynaecol Br Commonw 1971; 78:458-459

[24] Plate WP. Pheochromocytoma of the vagina. Gynaecologia 1995; 139:35-36

[25] Hosaka Y, Rainwater LM, Grant CS, et al. Pheochromocytoma: nuclear deoxyribo-nucleic patterns studied by flow cytometry. Surgery 1986; 100:1003-1010

[26] Jung WH, Yang WI, Park C, et al. DNA flow cytometry in pheochromocytoma and paraganglioma. Yonsei Med J 1992; 33:249-257

[27] Maier HC. Intra-thoracic pheochromocytoma with hypertension. Ann Surg 1949; 130:1059-1065

[28] Olsen JL, Salyer WR. Mediastinal paraganglioma (aortic body tumor). Cancer 1978; 41:2405-2412

[29] Gallivan MEV, Chun B, Rowden G, et al. Intra-thoracic, paravertebral malignant paraganglioma. Arch Pathol Lab Med 1980; 104:46-51

[30] Linnola RI, Keiser HR, Steinberg SM, et al. Histopathology of benign versus malignant sympatho-adrenal paragangliomas-clinico-pathological study of 120 cases including unusual histological features. Hum Pathol 1990; 21:1168-1180

[31] James R, Baker HL, Scanlon PW. The roentgenologic aspects of metastatic pheochromocytoma. Am J Roentgenol 1972; 115:783-793

[32] Coppage L, Shaw C, Curtis A. Metastatic disease to the chest in patients with extra-thoracic malignancy. J Thorac Imaging 1987; 2:24-37

[33] Libshitz HI, North LB. Pulmonary metastases. Radiol Clin North Am 1982; 20:437-451

[34] De Jong RS, Van den Bergen, Boender CA, et al. Extra-adrenal pheochromocytoma presenting as fulminant malignant disease with positive sputum cytology. J Intern Med 1991; 230:355-359

[35] Thompson NW, Allo MD, Shapiro B, et al. Extra-adrenal and metastatic pheochromocytoma: the role of [MIBG-I].sup.131] in localization and management. World J Surg 1984; 8:605-611

[36] Blom HJ, Karsdorp V, Birnie R, et al. Pheochromocytoma as a cause of pulmonary edema. Anesthesiology 1987; 42:646-650

[37] Hicks RJ, Wood B, Kalff V, et al. Normalization of left ventricular function following resection of a pheochromocytoma in a patient with dilated cardiomyopathy. Clin Nucl Med 1991; 16:413-416

[38] Radtke WE, Kazmier FJ, Rutherford BD, et al. Cardiovascular complications of pheochromocytoma crisis. Am J Cardiol 1975; 35:701-705

[39] Sardesai SH, Mourant AJ, Sivathandon T, et al. Pheochromocytoma and catecholamine induced cardiomyopathy presenting as heart failure. Br Heart J 1990; 63:234-237

[40] Sode J, Gitzen LC, Osbourne DD. Cardiac arrhythmias and cardiomyopathy associated with pheochromocytoma: report of three cases. Am J Surg 1967; 114:927-931

[41] Shub C, Williamson MD, Tajik AJ, et al. Dynamic left ventricular outflow tract obstruction associated with pheochromocytoma. Am Heart J 1981; 102:286-290

[42] Quezado ZN, Keiser HR, Parker MM. Reversable myocardial depression after massive catecholamine release from a pheochromocytoma. Crit Care Med 1992; 20:549-551

[43] Sloand EM, Thompson BT. Propranolol induced pulmonary edema and shock in a patient with pheochromocytoma. Arch Intern Med 1984; 144:173-174

[44] Rouby JJ, Gory GG, Gaveau T, et al. Dangerous rise in pulmonary wedge pressure following angiography in a patient with pheochromocytoma. Anesth Analg 1980; 59:154-156

[45] De Leeuw PW, Waltman FL, Birkenhager WH. Non-cardiogenic pulmonary edema as a sole manifestation of pheochromocytoma. Hypertension 1986; 8:810-812

[46] O'Hickey S, Hilton AM, Whittaker JS. Pheochromocytoma associated with adult respiratory distress syndrome. Thorax 1987; 42:157-158

[47] Feldman JM. Adult respiratory distress syndrome in a pregnant woman with pheochromocytoma. J Surg Oncol 1985; 29:5-7

[48] Harvey JN, Dean HG, Lee MR. Recurrence of asthma following removal of a noradrenaline secreting pheochromocytoma. Postgrad Med J 1984; 60:364-365

[49] Hargreaves DM. Pheochromocytoma with asthma. Anesth Intensive Care 1989; 17:90-92

[50] Sastre J, Azofra J, Sastra A. Pheochromocytoma and asthma [letter]. Chest 1985; 88:482

[51] Nishikawa T, Doshi S, Anzi Y. Recurrence of bronchial asthma after adrenelectomy for pheochromocytoma [letter]. Can Anesth Soc J 1986; 33:109-111

[52] Henderson WR, Shelhamer JH, Reingold DB, et al. Alpha-adrenergic hyper-responsiveness in asthma. N Engl J Med 1979; 300:642-647

[53] Grissom JR, Yamase HT, Prosser PR. Giant pheochromocytoma with sarcoidosis. South Med J 1979; 72:1605-1607

[54] Murray KM, Schillaci RF. Sarcoidosis and pheochromocytoma. West J Med 1987; 146:745-747

[55] Morris JA, Tymms DJ. Oat cell carcinoma, pheochromocytoma and carcinoid tumors-multiple APUD cell neoplasia: a case report. J Pathol 1980; 131:107-115

[56] Sheppard MN, Corrin B, Bennett MH, et al. Immunocytochemical localization of neuron specific enolase in small cell carcinomas and carcinoid tumors of the lung. Histopathology 1984; 8:171-181

[57] Min KW, Song J, Boisenberg M, et al. Adrenal cortical nodule mimicking small round cell malignancy on fine needle aspiration. Acta Cytol 1988; 32:543-546

[58] Zalcman G, Gamondes JP, Loire R, et al. Aorto-pulmonary chemodectoma (non-chromaffin paraganglioma): apropos of a case which followed an adrenal pheochromocytoma. Rev Mal Respir 1990; 7:283-286

[59] Dicke TE, Henry ML, Milton JP. Intracaval extension of pheochromocytoma simulating pulmonary embolism. J Surg Oncol 1987; 34:160-164

[60] Rote AR, Flint LD, Ellis FH Jr. Intracaval recurrence of pheochromocytoma extending into the fight atrium. N Engl J Med 1977; 296:1269-1271

[61] Bornemann M, Hill SC, Kidd GS. Lactic acidosis in pheochromocytoma. Ann Intern Med 1986; 105:880-882

[62] Keller U, Mall T, Walter M, et al. Pheochromocytoma and lactic acidosis. Br Med J 1978; 2:606-607

[63] Case records of the Massachusetts general hospital (case 9-1985): a 42 year old woman with hypertension, hemetemesis and metabolic acidosis. N Engl J Med 1985; 312:568-575

[64] Rosenblatt MB, Lisa JR, Trinidad S. Pitfalls in the clinical and histologic diagnosis of bronchogenic carcinoma. Dis Chest 1966; 49:396-404

[65] Trinidad S, Lisa JR, Rosenblatt MB. Bronchogenic carcinoma simulated by metastatic tumors. Cancer 1963; 16:1521-1529

[66] Zavala DC. Diagnostic fiberoptic bronchoscopy: techniques and results of biopsy in 600 patients. Chest 1975; 68:12-19

[67] Poe RH, Ortiz C, Israel RH, et al. Sensitivity, specificity and predictive values of bronchoscopy in neoplasm metastatic to lung. Chest 1988; 1:84-88

[68] Foncea V, Marc Bouloux P. Pheochromocytoma and paraganglioma. Baillieres Clin Endocrinol Metab 1993; 7:509-544

[69] Bravo EL, Tarazi RC, Gifford RW, et al. Circulating and urinary catecholamines in pheochromocytoma: diagnostic and pathophysiologic implications. N Engl J Med 1979; 301:682-686

[70] Werbel SS, Ober KP. Pheochromocytoma: update on diagnosis, localization and management. Med Clin North Am 1995; 79:131-153

[71] Quint LE, Glazer GM, Francis IR, et al. Pheochromocytoma and paraganglioma: comparison of MR imaging with CT and [I.sup.131] MIBG scintigraphy. Radiology 1987; 165:89-93

[72] Moulton JS, Moulton JS. CT of the adrenal glands. Semin Roentgenol 1988; 23:288-303

[73] McEwan AJ, Shapiro B, Sisson JC, et al. Radio-iodobenzylguanidine for scintigraphic location and therapy of adrenergic tumors. Semin Nucl Med 1985; 15:132-153

[74] Francis IR, Glazer GM, Shapiro B, et al. Complementary roles of CT and [I.sup.131] MIBG scintigraphy in diagnosing pheochromocytoma. AJR 1983; 141:719-725

[75] Welch TJ, Sheedy PF II, Van Heerdes JA, et al. Pheochromocytoma: value of computed tomography. Radiology 1983; 148:501-503

[76] Shapiro B, Copp JE, Sisson JC, et al. [Iodine.sup.131] MIBG for the localizing of pheochromocytoma: experience with 400 cases. J Nucl Med 1985; 26:576-585

[77] Chatal JF, Charbonnel B. Comparison of iodobenzylguanidine imaging with computed tomography in localizing pheochromocytoma, J Clin Endocrinol Metab 1985; 61:769-772

[78] Swensen SJ, Brown ML, Sheps SG, et al. Use of [I.sup.131] MIBG scintigraphy in the evaluation of suspected pheochromocytoma. Mayo Clin Proc 1985; 60:299-304

[79] Gough IR, Thompson NW, Shapiro B, et al. Limitations of [I.sup.131] MIBG scintigraphy in locating pheochromocytoma. Surgery 1985; 98:115-120

[80] Greenberg M, Moawad AH, Wieties BM, et al. Extra-adrenal pheochromocytoma: detection during pregnancy using MR imaging. Radiology 1986; 161:475-476

[81] Kadir S, Robinette C. Accuracy of angiography in the localization of pheochromocytoma. J Urol 1981; 126:789-793

[82] Boutros AR, Bravo EL, Zanetti G, et al. Perioperative management of 63 patients with pheochromocytoma. Cleve Clin J Med 1990; 57:613-617

[83] Sloand EM, Thompson BT. Propranolol induced pulmonary edema and shock in a patient with pheochromocytoma. Arch Intern Med 1984; 144:173-174

[84] Perry RR, Keiser HR, Norton JA, et al. Surgical management of pheochromocytoma with the use of metyrosine. Ann Surg 1990; 212:621-628

[85] Proye C, Vix M, Goropoulos A, et al. High incidence of malignant pheochromocytoma in a surgical unit: 26 cases out of 100 patients operated from 1971-1991. J Endocrinol Invest 1992; 15:651-663

[86] Averbuch SD, Steakley CS, Young RC, et al. Malignant pheochromocytoma: effective treatment with a combination of cyclophosphamide, vincristine and dacarbazine. Ann Intern Med 1988; 109:267-273

[87] Shapiro B, Sisson JC, Lloyd R, et al. Malignant pheochromocytoma: clinical, biochemical and scintigraphic characterization. Clin Endocrinol 1984; 20:189-203

[88] Timmis JB, Brown MJ and Allison DJ. Therapeutic embolization of pheochromocytoma. Br J Radiol 1981; 54:420-422

[89] Keiser HR, Goldstein DS, Wade JL, et al. Treatment of malignant pheochromocytoma with combination chemotherapy. Hypertension 1985; 7 (suppl 1):1-18

[90] Fischer M. Therapy of pheochromocytoma with [I.sup.131] metaiodobenzylguanidine. J Nucl Biol Med 1991; 35:292-294

[91] Lumbroso J, Schlumberger M, Tenenbaum F, et al. [I.sup.131] metaiodobenzylguanidine therapy in 20 patients with malignant pheochromocytoma. J Nucl Biol Med 1991; 35: 288-291

[92] Shapiro B, Sisson JC, Wieland DM, et al. Radio-pharmaceutical therapy of malignant pheochromocytoma with [I.sup.131] metaiodobenzylguanidine: results from ten years of experience. J Nucl Biol Med 1991; 35:269-276

[93] Lack EE, Cubilla AC, Woodruff JM, et al. Extra-adrenal paraganglioma of the retroperitoneum: a clinicopathologic study of 12 tumors. Am J Pathol 1980; 4:109-120

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