|Year : 2019 | Volume
| Issue : 1 | Page : 30-35
Pheochromocytoma: A single-center 20-year experience
Lung-Feng Cheng1, Shih-Che Tseng2, Chia-Cheng Yu3, Jen-Tai Lin4, Jeng-Yu Tsai1, I-Hsuan Chen1, Yin-Shen Chen1
1 Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
2 Kangshan Hospital of Kaohsiung County, Taiwan
3 Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung; Department of Pharmacy, Tajen University, Pingtung; School of Medicine, National Yang-Ming University, Taipei, Taiwan
4 Division of Urology, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung; School of Medicine, National Yang-Ming University, Taipei, Taiwan
|Date of Web Publication||2-Jan-2019|
Department of Surgery, Division of Urology, Kaohsiung Veterans General Hospital, No. 386 Ta-Chung 1st Road, Kaohsiung 81362
Source of Support: None, Conflict of Interest: None
Objective: Pheochromocytomas are catecholamine-producing neuroendocrine tumors arising from chromaffin cells of the adrenal medulla or extra-adrenal paraganglia. There is no large-scale study in Taiwan at present. Our retrospective analysis was focused on clinical characteristics of Taiwanese patients with pheochromocytoma. Method: We retrospectively reviewed 48 patients who were pathologically proved as pheochromocytoma at the Kaohsiung Veterans General Hospital between Jan. 1990 and Jan. 2014. Parameters including patient and tumor characteristics, clinical presentation, treatment and long-term followup results were collected from the medical records. Metastasis was confirmed by pathologic proof using surgical removal or percutaneous biopsy. Result: Thirty-one patients (64.5%) had adrenal and 17 (35.4%) had extra-adrenal pheochromocytoma. The locations of extra-adrenal pheochromocytoma included the retroperitoneum in 6 patients (35%), head and neck in 4 (23%), scrotum in 2 (12%), urinary bladder in 2 patients (12%), multiple organs in 2 (12%), and mediastinum in 1 (6%). The most common symptom was sustained hypertension (52%). Five patients were diagnosed as malignant pheochromocytoma due to pathologically proved metastasis. Conclusion: Pheochromocytomas are rare neuro-endocrine tumors with a highly variable clinical presentation. Prompt surgical removal of pheochromocytoma ensures a better prognosis. Radical surgical removal of tumor with vigorous control of blood pressure is the mainstay to improve symptoms and survival for malignant pheochromocytoma. Multi-center and large-scale studies were warranted and Lifelong followup is strongly recommended for all patients with pheochromocytoma.
Keywords: Extra-adrenal pheochromocytoma, malignant pheochromocytoma, paraganglia, pheochromocytoma
|How to cite this article:|
Cheng LF, Tseng SC, Yu CC, Lin JT, Tsai JY, Chen IH, Chen YS. Pheochromocytoma: A single-center 20-year experience. Urol Sci 2019;30:30-5
| Introduction|| |
Pheochromocytomas are catecholamine-producing neuroendocrine tumors arising from the chromaffin cells of the adrenal medulla, carotid and aortic bodies, organs of Zuckerkandl, and other extra-adrenal paraganglia occurring in the distribution of the sympathetic and parasympathetic systems. The clinical presentation of pheochromocytoma is highly variable. The common signs of catecholamine excess are hypertension, palpitations, tachycardia, headache, pallor, sweating, and feelings of panic or anxiety. Less common signs are nausea, flushing, fever, and constipation. Besides, severe cardiovascular complications caused by catecholamine excess include sudden death, arrhythmias, myocardial infarction, cardiac failure due to toxic catecholamine cardiomyopathy, dissecting aortic aneurysm, hypertensive encephalopathy, cerebrovascular accidents, and shock.
Malignant pheochromocytomas are rare. No histological feature or biochemical markers can distinguish benign from malignant tumors. Currently, the only criterion for malignancy is the presence of chromaffin cells at tissue sites where no chromaffin tissue originally exists. The most frequent sites of metastasis are bones (up to 70%), lung, liver, and lymph node., The natural clinical course of malignant pheochromocytoma is highly variable in patients with 5-year survival rates of 20%–50%.,
| Materials and Methods|| |
We retrospectively reviewed 48 patients who were pathologically proved as pheochromocytoma at the Kaohsiung Veterans General Hospital between January 1990 and January 2014. Parameters including patient and tumor characteristics, clinical presentation, treatment, and long-term follow-up results were collected from the medical records. Metastasis was confirmed by pathologic proof using surgical removal or percutaneous biopsy.
| Results|| |
A total of 48 patients were diagnosed as pheochromocytoma between January 1990 and January 2014. Thirty-one (64.5%) patients had adrenal and 17 (35.4%) had extra-adrenal pheochromocytoma. Among 31 patients of adrenal tumors, 14 (45%) were right sided, 15 (48%) were left sided, and the remaining 2 (7%) were bilateral. The locations of extra-adrenal pheochromocytoma included the retroperitoneum in 6 (35%) patients, head and neck in 4 (23%), scrotum in 2 (12%), urinary bladder in 2 (12%), multiple organs in 2 (12%), and mediastinum in 1 (6%) [Figure 1]. In two patients with extra-adrenal pheochromocytoma involving multiple organs, one presented with bilateral adrenal and neck tumors; the other had right adrenal tumors and one ipsilateral retroperitoneal tumor. The mean age at diagnosis was 49.7 years (range 13–88 years). The mean tumor diameter is 5.7 cm (range 0.7–19.3 cm). The male:female ratio is 23:25 [Table 1]. The most common symptom was sustained hypertension (52%). Fifteen (31%) patients were asymptomatic pheochromocytoma. Twenty-seven (56%) patients had the symptoms of catecholamine secretion, especially in the group of adrenal pheochromocytoma [Table 2]. Five patients were diagnosed as malignant pheochromocytoma due to pathologically proven metastasis [Table 3]. Four of them presented clinical symptoms as recurrent poorly controlled high blood pressure, hot flush, and sweating. One patient was found by regular follow-up imaging without clinical symptoms. The 24-h urine vanillyl mandelic acid (VMA) showed elevated in two of recurrent cases. Only one of them was primarily of extra-adrenal origin; the remaining four patients were of adrenal origin. The most common metastatic sites are lymph node (60%), bone (40%), liver (20%), and lung (20%). Resectable metastatic lesions were removed by surgery or ablated by radiofrequency therapy. Unresectable lesions were treated with chemotherapy (combination of cyclophosphamide, vincristine, and dacarbazine) and radiotherapy. Two patients died of metastatic disease 1 year and 4 years, respectively, after diagnosis of malignant pheochromocytoma. The other three patients were alive: A 29-year-old male with local recurrence and lymph node metastasis received surgical resection and well blood pressure control; a 56-year-old female underwent radiofrequency ablation for local recurrence and radiotherapy for right acetabulum metastasis; and a 13-year-old male with multiple metastases received no further treatment except vigorous control of blood pressure.
|Figure 1: Distribution of extra-adrenal pheochromocytoma. *Multiple group: Bilateral adrenal tumors and bilateral neck tumors (n = 1), right adrenal tumors and one retroperitoneal tumor (n = 1)|
Click here to view
|Table 3: Clinical characteristics of patients with malignant pheochromocytoma|
Click here to view
| Discussion|| |
Pheochromocytoma is regarded as 10% tumor traditionally. The rule of ten is that approximately 10% of pheochromocytomas are malignant, 10% are bilateral, 10% are extra-adrenal, 10% are not associated with hypertension, and 10% are hereditary. Recent studies have challenged the concept of pheochromocytoma as the 10% tumor., In our study, the largest series report on pheochromocytoma with long-term follow-up in Taiwan, 10.4% of pheochromocytoma are malignant, 6.25% are bilateral, and 35% are extra-adrenal. Only one patient was diagnosed as having hereditary pheochromocytoma; his mother had bilateral adrenal pheochromocytomas and his brother had medullary thyroid carcinoma and unilateral adrenal pheochromocytoma. He presented with bilateral adrenal pheochromocytomas, bilateral neck extra-adrenal pheochromocytomas, and hypercalcemia induced by hyperparathyroidism. Multiple endocrine neoplasia type 2 was impressed by clinical presentation.
Most clinical symptoms and signs of pheochromocytoma are caused directly by the action of secreted catecholamines. Metabolic effects, such as hypercalcemia, lactic acidosis, and weight loss, also occurred in patients with pheochromocytoma. Because the use of medical imaging increases dramatically in the past decades, the number of adrenal incidentalomas is increasing. About 25% of all pheochromocytomas were found incidentally during imaging studies for unrelated disorder.,, In the present study, 31.35% were adrenal incidentalomas [Table 2]. The prevalence of asymptomatic pheochromocytoma in our study was higher than other studies.,, Catecholamine-secreting extra-adrenal pheochromocytomas account for 20% of all catecholamine-secreting tumors. The symptoms related to catecholamine, such as hypertension, headache, sweating, and palpitation, were less in the extra-adrenal group. As for our results, some differences of the tumor prevalence and clinic characteristics were found in comparison with other studies. Was the difference caused by ethnic variation, lifestyle, or study bias? Multicenter and large-scale studies may be required to clarify this issue.
Extra-adrenal pheochromocytomas are usually located within the abdomen in association with the celiac, superior mesenteric, inferior mesenteric ganglia, and organs of Zuckerkandl. Approximately 10% of Pheochromocytoma are in the thorax, 1% is within the urinary bladder, and <3% are in the neck, usually in association with the sympathetic ganglia or the extracranial branches of the ninth cranial nerves. Primary involvement of the urinary bladder is rare, accounting for <0.06% of all bladder tumors and <1% of all pheochromocytomas. The common symptoms of extra-adrenal pheochromocytoma of the urinary bladder are painless gross hematuria, hypertension, and a drop in blood pressure occurred during the operation., Usually, the tumor is located submucosally with protruding into the bladder lumen. The mucosal surface may be smooth or ulcerated [Figure 2]. Preoperative diagnosis by clinical presentation and adequate preparation are very important to make the surgery safe. However, 27% of urinary bladder pheochromocytomas do not feature any hormonal activity before operation. Morbidity complicated with catecholamine secretion may happen during cystoscopy or biopsy occasionally. Fatal hypertensive crisis was reported in rare cases during operation. In our cases, two patients with extra-adrenal pheochromocytoma of urinary bladder were diagnosed: one was asymptomatic and the other one suffered from intermittent painless gross hematuria for 1 month. Both patents were treated with transurethral resection of bladder tumor. No blood pressure fluctuation was noted during operation. However, blood pressure dropped after operation in the symptomatic patient and it recovered after fluid resuscitation. There was no local recurrence or distant metastasis after operation.
|Figure 2: Urinary bladder pheochromocytoma. The tumor is located submucosally with protruding into the bladder lumen|
Click here to view
The prevalence of malignancy in pheochromocytoma is reported to range between 2% and 26%., Only the presence of metastases of chromaffin tissue at sites where no chromaffin tissue should be expected establishes a definite diagnosis of malignant pheochromocytoma. The most common metastatic sites for chromaffin-cell tumors are local lymph nodes, bone, liver, and lung., In our study, the common metastatic sites were lymph nodes (60%), bone (40%), liver (20%), and lung (20%). The 5-year survival rates of malignant pheochromocytoma are 20%–50%., There have been several attempts to trying distinguish between benign and malignant tumors at the time of diagnosis. Many studies for the prediction of malignancy have focused on parameters, such as patient and tumor characteristics, biochemistry, imaging, and histology. The most reliable predictors are still the size (tumor size >5 cm in diameter) and location of the tumor (extra-adrenal pheochromocytoma) currently., These metastases usually occur in the first 2 years, but can happen as late as 40 years after the original diagnosis., About 80% of the time interval for malignant pheochromocytoma was within 10 years.
Prognosis in patients with malignant pheochromocytoma is difficult to predict, but is known to be poor secondary to local recurrence or widespread metastasis.,
Treatments for malignant pheochromocytoma include surgical debulking, pharmacologic control of hormone-mediated symptoms, targeted methods such as external irradiation or radiofrequency tumor ablation, and systemic antineoplastic therapy. Surgical debulking is widely regarded as a mainstay of palliative therapy for malignant pheochromocytomas. The targeted therapy with radiofrequency ablation may be safely performed for metastatic pheochromocytoma with careful attention to periprocedural blood pressure monitoring and management. Furthermore, preprocedural preparation was needed and premedicated for 7–21 days with α-adrenergic inhibition (phenoxybenzamine), β-adrenergic inhibition (atenolol), and α-methyl-paratyrosine to decrease the risk of hypertensive crisis. Except hypertensive crisis, the risks of needle tract seeding and bleeding can be decreased by cauterizing the needle tract before termination of the procedure.
123 I-metaiodobenzylguanidine (MIBG) radioconjugate therapy is the most studied method of targeted therapy. The phase II trial to evaluate the safety and efficacy of high dose of MIBG showed that the overall complete response (CR) plus partial response rate was 22% and the estimated 5-year overall survival rate was 64%. The other retrospective studies reported response rate to MIBG therapy ranged from 22% to 48%. The adverse effects of MIBG therapy are asthenia, nausea, vomiting, hematologic and thyroid dysfunction, and to a lesser extent, second cancer, hypertensive crisis, sepsis, and pulmonary toxicity.,,,,,
The systemic chemotherapy with cyclophosphamide–vincristine–dacarbazine (CVD) regimen to treat malignant pheochromocytoma was proposed by Averbuch et al. The results showed 55% of partial or CR rates. The median overall survival duration was 3.3 years. One alternative to the CVD regimen may be temozolomide, an oral alternative with less toxicity to intravenous dacarbazine, which had been reported to have similar response rate to CVD regimen by Gustave Roussy Institute.
Combination of temozolomide and thalidomide has been reported to have 33% radiologic response rate. The sunitinib study showed a median overall survival of 26.7 months and progression-free survival of 4.1 months (95% confidence interval = 1.4–11.0).
In our cases, the youngest patient at initial diagnosis as pheochromocytoma was 13 years old. He was admitted for spontaneous intracranial hemorrhage. Multiple right adrenal tumors and one ipsilateral retroperitoneal tumor were found after imaging survey. Right adrenalectomy and retroperitoneal tumor resection were done and pheochromocytoma was confirmed by pathology report. However, recurrent headache, sweating, and hypertension with para-aortic lymph node and liver metastases happened about 6 years later. He declined surgical intervention, chemotherapy, or radiation therapy due to personal reason. Only antihypertensive agents for blood pressure control were instituted. Fortunately, the metastatic lesions were stable with slow progression. According to our limited experience, vigorous blood pressure control is the mainstay of prolongation of survival for unresectable malignant pheochromocytoma.
The main factors for tumor progression are still unclear. There are limited studies addressing with the predictive factors of progression of malignant pheochromocytoma. There is no difference in overall survival between adrenal and extra-adrenal malignant pheochromocytomas. However, the outcome worsens with increasing tumor size. More large-scale clinical studies will be required to identify the factors of progression of malignant pheochromocytoma and effective treatments.
The limitations of our study are a retrospective manner and single-center data. Genetic tests were unavailable for hereditary pheochromocytoma survey. The number of cases is also limited. Multicenter and large-scale studies were warranted.
| Conclusion|| |
To the best of our knowledge, the current study is the largest series report on pheochromocytoma with long-term follow-up in Taiwan. Pheochromocytomas are rare neuroendocrine tumors with a highly variable clinical presentation. Prompt surgical removal of pheochromocytoma ensures a better prognosis. Although the malignant potential is low, the prognosis of metastasis is poor, and no optimal treatment can be provided. Treatment with radiotherapy or combination chemotherapy may have limited effect. Radical surgical removal of tumor with vigorous control of blood pressure is the mainstay to improve symptoms and survival for malignant pheochromocytoma. Lifelong follow-up is strongly recommended for all patients with pheochromocytoma.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet 2005;366:665-75.
Harari A, Inabnet WB 3rd
. Malignant pheochromocytoma: A review. Am J Surg 2011;201:700-8.
Edström Elder E, Hjelm Skog AL, Höög A, Hamberger B. The management of benign and malignant pheochromocytoma and abdominal paraganglioma. Eur J Surg Oncol 2003;29:278-83.
Scholz T, Eisenhofer G, Pacak K, Dralle H, Lehnert H. Clinical review: Current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 2007;92:1217-25.
Elder EE, Elder G, Larsson C. Pheochromocytoma and functional paraganglioma syndrome: No longer the 10% tumor. J Surg Oncol 2005;89:193-201.
Benn DE, Robinson BG. Genetic basis of phaeochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab 2006;20:435-50.
La Batide-Alanore A, Chatellier G, Plouin PF. Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens 2003;21:1703-7.
Mantero F, Terzolo M, Arnaldi G, Osella G, Masini AM, Alì A, et al.
A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab 2000;85:637-44.
Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF, et al.
Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005;90:2110-6.
Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR, et al.
The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr Rev 2004;25:309-40.
Young AL, Baysal BE, Deb A, Young WF Jr. Familial malignant catecholamine-secreting paraganglioma with prolonged survival associated with mutation in the succinate dehydrogenase B gene. J Clin Endocrinol Metab 2002;87:4101-5.
Tsai CC, Wu WJ, Chueh KS, Li WM, Huang CH, Wu CC, et al.
Paraganglioma of the urinary bladder first presented by bladder bloody tamponade: Two case reports and review of the literatures. Kaohsiung J Med Sci 2011;27:108-13.
Onishi T, Sakata Y, Yonemura S, Sugimura Y. Pheochromocytoma of the urinary bladder without typical symptoms. Int J Urol 2003;10:398-400.
Westphal SA. Diagnosis of a pheochromocytoma. Am J Med Sci 2005;329:18-21.
Naqiyah I, Rohaizak M, Meah FA, Nazri MJ, Sundram M, Amram AR, et al.
Phaeochromocytoma of the urinary bladder. Singapore Med J 2005;46:344-6.
Eisenhofer G, Bornstein SR, Brouwers FM, Cheung NK, Dahia PL, de Krijger RR, et al.
Malignant pheochromocytoma: Current status and initiatives for future progress. Endocr Relat Cancer 2004;11:423-36.
Lehnert H, Mundschenk J, Hahn K. Malignant pheochromocytoma. Front Horm Res 2004;31:155-62.
Korevaar TI, Grossman AB. Pheochromocytomas and paragangliomas: Assessment of malignant potential. Endocrine 2011;40:354-65.
Tanaka S, Ito T, Tomoda J, Higashi T, Yamada G, Tsuji T, et al.
Malignant pheochromocytoma with hepatic metastasis diagnosed 20 years after resection of the primary adrenal lesion. Intern Med 1993;32:789-94.
Zelinka T, Musil Z, Dušková J, Burton D, Merino MJ, Milosevic D, et al.
Metastatic pheochromocytoma: Does the size and age matter? Eur J Clin Invest 2011;41:1121-8.
Nakane M, Takahashi S, Sekine I, Fukui I, Koizumi M, Kage K, et al.
Successful treatment of malignant pheochromocytoma with combination chemotherapy containing anthracycline. Ann Oncol 2003;14:1449-51.
Venkatesan AM, Locklin J, Lai EW, Adams KT, Fojo AT, Pacak K, et al.
Radiofrequency ablation of metastatic pheochromocytoma. J Vasc Interv Radiol 2009;20:1483-90.
Gonias S, Goldsby R, Matthay KK, Hawkins R, Price D, Huberty J, et al.
Phase II study of high-dose [131I] metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol 2009;27:4162-8.
Baudin E, Habra MA, Deschamps F, Cote G, Dumont F, Cabanillas M, et al.
Therapy of endocrine disease: Treatment of malignant pheochromocytoma and paraganglioma. Eur J Endocrinol 2014;171:R111-22.
Krempf M, Lumbroso J, Mornex R, Brendel AJ, Wemeau JL, Delisle MJ, et al.
Use of m-[131I] iodobenzylguanidine in the treatment of malignant pheochromocytoma. J Clin Endocrinol Metab 1991;72:455-61.
Gedik GK, Hoefnagel CA, Bais E, Olmos RA 131I-MIBG therapy in metastatic phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2008;35:725-33.
Wakabayashi H, Taki J, Inaki A, Nakamura A, Kayano D, Fukuoka M, et al.
Prognostic values of initial responses to low-dose (131) I-MIBG therapy in patients with malignant pheochromocytoma and paraganglioma. Ann Nucl Med 2013;27:839-46.
Plouin PF, Fitzgerald P, Rich T, Ayala-Ramirez M, Perrier ND, Baudin E, et al.
Metastatic pheochromocytoma and paraganglioma: Focus on therapeutics. Horm Metab Res 2012;44:390-9.
Averbuch SD, Steakley CS, Young RC, Gelmann EP, Goldstein DS, Stull R, et al.
Malignant pheochromocytoma: Effective treatment with a combination of cyclophosphamide, vincristine, and dacarbazine. Ann Intern Med 1988;109:267-73.
Huang H, Abraham J, Hung E, Averbuch S, Merino M, Steinberg SM, et al.
Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: Recommendation from a 22-year follow-up of 18 patients. Cancer 2008;113:2020-8.
Hadoux J, Favier J, Scoazec JY, Leboulleux S, Al Ghuzlan A, Caramella C, et al.
SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer 2014;135:2711-20.
Kulke MH, Stuart K, Enzinger PC, Ryan DP, Clark JW, Muzikansky A, et al.
Phase II study of temozolomide and thalidomide in patients with metastatic neuroendocrine tumors. J Clin Oncol 2006;24:401-6.
Ayala-Ramirez M, Chougnet CN, Habra MA, Palmer JL, Leboulleux S, Cabanillas ME, et al.
Treatment with sunitinib for patients with progressive metastatic pheochromocytomas and sympathetic paragangliomas. J Clin Endocrinol Metab 2012;97:4040-50.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]