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Clinical Experience With Incidentally Discovered Pheochromocytoma
OO22-5347/97/1575- 1 W 0 3.W/O
Vol. 157, 1566-1568, May 1997 Printed in U.SA,
THEJOLWAL OF UROLOGY Copyright 0 1997 by h E R I c m UROLOCICAL kSSocl~TloS, INC.
CLINICAL EXPERIENCE WITH INCIDENTALLY DISCOVERED PHEOCHROMOCYTOMA AKIRA MIYAJIMA,* JUN NAKASHIMA, SHIRO BABA, MASAAKI TACHIBANA, KAORU NAKAMUM AND MAsARU M U M From the Department of Urology, Keio University School of Medicine, Shinjuku. Tokyo. Japan
ABSTRACT
Purpose: We reviewed 17 resected pheochromocytomas comprising 7 from symptomatic patients, and 10 unsuspected and incidentally discovered tumors. We compared various parameters concerning these 2 groups and investigated the features of the incidentally discovered pheochromocytoma. Materials and Methods: Patient gender and age, clinical symptoms and signs, tumor localization, detection methods, findings on imaging studies, urinary catecholamine concentrations, results of metoclopramide stimulation tests, treatments at operation and tumor size were evaluated. Furthermore, we compared the clinically diverse aspects arising between the symptomatic and incidentally discovered pheochromocytomas. Results: The 24-hour urinary noradrenaline and vanillylmandelic acid levels in the incidental cases tended to be lower than those in the symptomatic cases, while 24-hour urinary dopamine was significantly less (468 -C 221 compared t o 1,558 5 899 pg./day, respectively). Typical symptoms of pheochromocytoma were noted in 6 patients (60%) in the incidental tumor group. The incidental cases had a markedly high false-negative rate (71%) as noted by the metoclopramide stimulation test, although the symptomatic cases had a 100% positive rate. On the other hand, the average diameter of incidental tumors was significantly larger than that of the symptomatic lesions (55.5 -C 19.1 versus 35.9 -C 12.1 mm., respectively). Conclusions: Clinical signs and findings in patients with incidental tumors were weaker than those with symptomatic disease although most incidental tumors functioned. Lower urinary catecholamine values in the incidental tumors were consistent with these results. However, the surgical risk for incidental tumors was the same as that for symptomatic lesions. Therefore, patients with incidentally discovered pheochromocytomas scheduled to undergo surgery should be treated accordingly. KEY WORDS:pheochromocytoma, adrenal gland neoplasms, carcinoma
Advances in imaging diagnosis, high resolution ultrasonography, computerized tomography (CT) and magnetic resonance imaging (MRI) have resulted in a significant increase in incidentally discovered adrenal tumors, including pheochromocytoma.1.2 I t has been stated that a n adrenal tumor will be discovered incidentally for an unrelated reason in at least 2%'of patients undergoing abdominal CT and that the prevalence of pheochromocytoma in patients with a n incidentally discovered adrenal tumor should be approximately 6.5q.3 On the other hand, As0 and Homma reported a 2396 pheochromocytoma discovery rate for all incidentally discovered adrenal tumors in Japan.2 Thus, it is assumed that many incidentally discovered adrenal tumors may not be absolutely nonfunctioning.4 Identification of incidental pheochromocytomas among the hormonally active tumors is important from the viewpoint of perioperative treatment and the malignant potential. However, to our knowledge no clinical investigation has fully elucidated the characteristics of incidentally discovered pheochromocytomas. To evaluate the difference between the incidentally discovered and symptomatic pheochromocytomas we retrospectively reviewed 17 patients with pheochromocytomas who presented within the last 5 years.
MATERIALS AND METHODS
Incidentally discovered adrenal tumors were defined as those that were detected primarily during the course of an evaluation for a n unrelated disease or a routine physical examination. Therefore, this definition included previously unsuspected adrenal masses found a t any examination or during treatment even if the patient had symptoms or signs retrospectively caused by the adrenal tumor.2 Patients who presented with typical symptoms suspicious for a pheochromocytoma that was confirmed by examination were classified into the symptomatic group. Accordingly, we studied 10 incidental and 7 symptomatic pheochromocytomas that were surgically resected and pathologically diagnosed at our institute between 1991 and 1995. Case histories were reviewed for age at diagnosis; gender; presence of typical symptoms, including hypertension, headache and palpitation; findings on ultrasonography, CT, MRI and metaiodobenzylguanidine (MIBG) scans; result of a metoclopramide stimulation test; tumor localization; concentrations of 24-hour urinary catecholamine (adrenalin, noradrenalin and dopamine) and vanillylmandelic acid; preparation of adrenergic antagonist; intraoperative blood pressure elevation; operative blood loss; necessity for blood transfusion or dopamine infusion postoperatively; diameter of the surgical specimen, and pathological diagnosis. Data on 24-hour ~ r i Accepted for publication October 11, 1996. * Re uests for reprints: Department of Urology, National Defense nary catecholamine concentration, operative blood loss and MedicA College, 3-2, Namiki. Tokorozawa. Saitama 359, Japan. diameter of the surgical specimen were reported as mean 1566
CLINICAL EXPERIENCE WITH INCIDENTALLY DISCOVERED PHEOCHROMOCYTOMA
or minus standard deviation. Variables for different were compared using Student’s t test or the chisquare test. A level of p <0.05 was considered statistically significant. RESULTS
1567
toma. During the operation blood pressure was elevated in 5 symptomatic (71.4%) and 7 incidental (70%) cases. Baseline systolic and diastolic blood pressures were decreased in all cases with the vasodilator after resection of the tumors. Average blood loss during the operation was 488 2 389 gm. in the symptomatic and 740 2 798 gm.in the incidental groups (difference not significant). Blood t r a n s h i o n was necessary in 1 case in each group. In 3 symptomatic (42.9%) and 8 incidental (80%) cases blood pressure was maintained by continuous dopamine infusion after surgical excision. Mean diameter of the surgical specimen was 35.9 2 12.1 mm. in the symptomatic and 55.5 2 19.1 nun. in the incidental groups, which was significantly Merent. All tumors were pathologically diagnosed as pheochromocytomas.
The 3 men and 4 women with symptomatic tumors were 16 to 68 years old (mean age 41.4 2 14.7), and the 5 men and 5 women with incidental tumors were 37 to 69 years old (mean age 57.2 t 10.0). Accordingly, we believe that mean age in the symptomatic group is likely to be younger than that in the incidental group although the difference in our patients was not significant. Concerning clinical symptoms and signs, all symptomatic patients had typical hypertension related symptoms, while 6 with incidental disease (60%) presented with hypertension. Of these patients 3 had low grade fever DISCUSSION without typical symptoms and 1 was completely asymptomImprovements in imaging studies have resulted in an inatic. Five incidental pheochromocytomas were primarily found crease in incidentally discovered adrenal or retroperitoneal on CT and 5 on ultrasonography. These imaging studies were tumors. The prevalence of pheochromocytomas was reportdone mainly during routine annual physical examinations or edly 6.5%3 and this rate continues to increase. In our country for evaluation of unrelated diseases. Most incidental and the rate of incidentally discovered pheochmmocytomas has Symptomatic tumors were localized in the adrenal glands increased to more than 20% of all incidentally discovered except for 2 in the para-aortic area. AU cases were delineated adrenal tumors.2 Although unexpected adrenal tumors were by an iso-hypoechoicmass generated by ultrasonography and believed to be nonfbctioning endocrinologically, they actuby an iso-low density mass produced by CT. In most cases ally may not be nonfunctioning after all. These completely MRI demonstrated a low isointensity mass in the T1-weighted silent pheodmmocytomas are reportedly rare.6 Our incidenimage and a high intensity mass in the T2-weighted image. tally discovered pheochmmocytomas were mostly functionIn 1 incidental case the T1-weighted image denoted a high ing. Because of the dramatic symptoms functional tumorsare intensiti mass. MIBG scanning yielded 100 and 75% positive usually small when detected, whereas nonfunctional tumors rates in the symptomatic and incidental tumor groups, re- may be large.6 In our study the mean diameter of incidental tumors was also significantly larger than that of symptomspectively. The 24-hour urinary excretion of dopamine, adrenaline atic tumors. Crout and Sjoerdsma noted that pheochmmocyand noradrenaline was measured in all patients. Mean uri- tomas 50 gm.or larger are often asymptomatic because senary dopamine in the symptomatic tumors (1,558 2 899 pg. creted catecholamines are metabolized within the tumor.7 In daily) was significantly greater than that in the incidental contrast, tumors smaller than 50 gm. have slow turnover cases (468 5 221 pg. daily). No significant difference was rates and release fiee catecholamines into the circulation, observed in the mean values of adrenaline, noradrenaline exhibiting persistent symptoms and signs.8 The clinical diagnosis of pheochromocytoma is based on the and vanillylmandelic acid. Urinary dopamine levels were normal (316 to 1,272 pg. daily) in 3 symptomatic and all 10 subjective evaluation of signs and symptoms. When one enincidental tumors, and elevated in 4 symptomatic cases (p counters a patient with an incidentally discovered, possible <0.05). The 24-hour urinary noradrenalin levels were ele- pheochromocytomaone should carefully note the history and vated (more than 145 pg. daily) in all 7 symptomatic (1,527 ? perform a physical examination initially. Of our patients 1,467 pg. daily) and in 8 incidental (284 2 239 pg. daily) with incidentally discovered pheochmmocytomas 60% had tumors. This difference was not significant. If the borderline typical symptoms associated with the disease, consisting of was set at the 2-fold elevation of the upper limit then 6 of 7 hypertension, headache, palpitations and sweating attack, symptomatic (85.7%) compared to 2 of 10 incidental (20%) although 10%of patients were reported to be norm0tensive.Q tumors had more than a 2-fold elevated noradrenalin level The reasons for finding these normotensive patients despite and this difference was significant (p <0.05). There was no high circulating levels of catecholamines are reported to insignificant difference in urinary adrenaline and vanillylman- clude hypovolemia and nonresponsiveness due to prolonged delic acid values between the 2 groups. The results of the stimulation.7 Also multiple biochemical tests, including metoclopramide stimulation test were positive in 100 and plasma and %hour urinary catecholamine determinations, 29% of the symptomatic and incidental cases, respectively must be performed. Incidental tumors tend to exhibit lower 24hour urinary catecholamine values than symptomatic tu(skTS.cant difference, p <0.05). Hypertension was noted in 6 of 10 patients with incidental mors. Mean urinary dopamine was signhantly less in the tumors (see table). Preparation with an a-adrenergic antag- incidental than in the symptomatic cases, and the incidence onist or calcium channel blockers was done in all symptom- of positive urinary dopamine levels between the 2 groups was atic and 8 incidental cases, while a-adrenergic antagonists significantly different. All symptomatic and most incidental and calcium channel blockers were not used in the remaining tumors showed positive 24hour urinary noradrenaline lev2 incidental cases with no typical findings of pheochromocy- els, demonstrating high sensitivity (88.2%). However, significantly fewer incidental than symptomatic tumors had more than a 200% elevated noradrenaline level. These findings suggest that incidentally discovered pheochmmocytomas function despite the lower potential. When 1of these clinical Clinical symptom and signs in patients with pheochromocytoma and laboratory findings suggests pheochmmocytoma further No. Pheochmmocytonm evaluation should be performed.10 Particularly MRI can betSymptoms symptomatic Incidental ter delineate the tissue character and extent of the n m plasm,” and MIBG can be useful in determining the funcHypertension 6 6 tional character of a tumor and locating occult secondary or Headache 2 0 Fever 0 3 metastatic sites.8 Moreover, some provocation tests (metode None 0 1 pramide and glucagon) or a suppression teet (clonidine)
1568
CLINICAL EXPERIENCE WITH INCIDENTALLY DISCOVERED PHEOCHROMOCYTOMA
should be done. The metoclopramide stimulation test reportedly yields excellent specifkity.12 On the other hand, our incidental cases showed a high false-negative rate (71.4%) with the metoclopramide stimulation test and the possibility of a false-negative case (28.6%)with MIBG scanning. These results are likely to be produced by the low endocrinological potential of incidentally discovered pheochromocytomas, although functions exceeded the normal range. Indeed, we should integrate the results of various biochemical tests and diverse radiological studies into the diagnosis of a pheochromocytoma at this stage. If an incidentally discovered tumor is proved to be a functioning pheochmmocytoma, treatment should theoretically be the same as that for symptomatic disease. F'razosin, an a-adrenergicblocking agent, has been used preoperatively as an alternative to phenoxybenzamine at our institute. Pretreatment with padrenergic blockers is considered when arrhythmia or tachycardia becomes a problem. Intraoperativemanagement of these cases involves several concerns. Central vein pressure and arterial pressure monitoring should be used routinely to evaluate the hemodynamic parameters and cardiac function. Enflusane or isoflurane should be used for anesthesia because both decrease myocardid irritability.*3Intraoperative hypertension is believed to be treated with phentolamine or nitroprueside,and propanolo1 is excellent for the treatment of intraoperative supraventricular tachycardia, while patients with ventricular arrhythmias receive lidocaine. However, the use and regimen of these pharmacological agents vary with the administering institution. For persistent hypotension following tumor removal, volume replacement is required in conjunction with carefid cardiovascular monitoring. CONCLUSIONS
We suggest that retroperitoneal incidentally discovered tumors that cannot be ruled out as pheochromocytomas should be comprehensively evaluated. Incidentally discovered pheochromocytomas should also be treated prudently due to the inherent unpredictable risk.
DTPA-enhanced dynamic studies. Radiology, 171: 675, 1989. H.,Itaya, Y.,Suzuki, H., Kondo, K. and Saruta, T.: Meklopramide in the diagnosis of pheochromocytoma. Jap. Heart J., 26: 557, 1985. 13. Vaughan, E. D., Jr. and Blumenfeld, J. D.: The adrenals. In: Campbell's Urology, 6th ed.Edited by P. C. Walsh, A. B. Fktik, T. A. Stamey and E. D. Vaughan, Jr. Philadelphia: W. B. Saunders Co., vol. 3, chapt. 64,pp. 2360-2412, 1992.
12. Kawabe,
EDITORIAL COMMENT These interesting observations confirm the clinical dictum that patients with incidental adrenal masses should be evaluated to rule out pheochromocytoma (reference 3 in article). In large series of patients with clinically apparent pheochromocytomasthe most common clinical finding is hypertension, sustained or intermittent, which is found in 90 to 95% of cases (reference 13 in article). In contrast, of the 10 patients with incidental pheochromocytomas in this series only 60% presented with hypertension. Moreover, urinary catecholamine levels were also higher in the symptomatic patients. Urinary norepinephrine levels were elevated in 8 of the 10 patients with incidental lesions, although they were rarely (2 of 10) twice the normal level. It would appear that careful evaluation of epinephrine, norepinephrine and vanillylmandelic acid w i l l identify integrated hypersecretion of catecholamines in most patients with incidental lesions. Altbough not measured in this study, plasma catecholamine levels would be assumed to be less accurate in these normotensive patients. MRI showed the characteristic bright "2-weighted image in these patients and remains the appropriate imaging study for those with suspected pheochromoeytomas, symptomatic or incidental (reference 13 in article). The final and important point made by the authors is that these patients, although normotensive preoperatively, should still be expected to respond intraoperatively in a fashion similar to patients with symptomatic pheochromocytomas. Therefore, preoperative preparation with a-adrenergic antagonists or calcium channel blockera should be done in patients with incidental pheochmmocytomas. Moreover, the anesthesiologist should be fully prepared to respond with appropriate drugs in these patients just as they would in a patient with a symptomatic pheochromocytoma. E. Darracott Vaughan, Jr. Department of Urology New York HospitallCornell Medical Center New York,New York
REFERENCES
1. Gross, M. D. and Shapiro, B.: Clinical Review 50: clinically silent adrenal masses. J. Clin. Endow. Metab., 77: 885, 1993. 2. Aso, Y. and Homma, Y.: A survey on incidental adrenal tumors in Japan. J. Urol., 147: 1478, 1992. 3. Ross, N. S. and Aron, D. C.: Hormonal evaluation of the patient with a n incidentally discovered adrenal mass. New Engl. J. Med., 325: 1401, 1990. 4. Kobayashi, S.,s k i , T., Nonomura, K., Gotoh, T., Togashi, M. and Koyanagi, T.: Clinical experience of incidentally discovered adrenal tumor with particular reference to cortical function. J. Urol., 1M): 8, 1993. 5. Nagashima, F.,Hayashi, J., Araki,Y., Sugihara, T., Nomura, M., Morichika, Y., Inoue, J., Shibata, S. and Akagi, E.: Silent mixed ganglioneuroma/pheochromromocytomawhich produces a vasoactive intestinal polypeptide. Intern. Med., 32: 63,1993. 6. Whalen, R. K., Althausen, A. F. and Daniels, G. H.: Extraadrenal pheochromocytoma. J. Urol., 147: 1,1992. 7. Crout, J. R. and Sjoerdsma. A.: Turnover and metabolism of catecholamine in patients with pheochromocytoma. J. Clin. Invest., 4 3 94, 1964. 8. Bravo, E. L.: Pheochmocybma: new concepts and future trends. Kidney Int., 40:544, 1991. 9. Scott, H.W., Jr., Oates, J. A., Nies, A. S., Burko, H., Page, D. L. and Rhamey, R.K:Pheochromocytoma:present diagnosis and management. Ann. surg., 1sS:587, 1976. 10. Bravo, E. L. and Gif€ord, R. W., Jr.: Current concepts. Pheochromocytoma: diagnosis, localization and management. New Engl. J. Med., 311: 1298, 1984. 11. Krestin, G. P., Steinbrich, W. and Friedmann, G.: Adrenal masses: evaluation with fast gradientecho MR imaging and Gd-
REPLY BY AUTHORS
Our results demonstrate that urinary catecholamine levels in incidentally found cases were lower than those in symptomatic cases because of weak function. Accordingly, it can be surmised that the incidence of hypertension in incidentally discovered cases may be lower than that stated in the comment. However, 15 of our 17 cases (88%)had function, which is consistent with the 90 to 95% rate of hypertension noted. Mean values plus or minus standard deviation of plasma adrenaline, noradrenaline and dopamine in our series were 22.7 -t 59.7, 4.4 ? 5.6 and 0.7 ? 1.9 ngJml. in symptomatic cases and 0.4 2 0.7, 1.2 2 1.4 and 0 ng.1ml. in incidentally found cases (no significant difference). The limited sensitivity and specificity of plasma catecholamine for diagnosing pheochromocytoma have been well established.' MRI showed the characteristic bright T2-weighted image in our patients. It has also been reported that most neurogenic tumors are delineated brightly on T2-weighted images.2 Pheochromocytoma reportedly showed marked enhancement in the early phase on TIweighted images after the administration of gadolinium pentetic acid (reference 11 in article). Thus, in making the diagnosis of pheochromocytoma we integrated the results of various biochemical tests and diverse radiological studies a t this stage. 1. Krakoff, L. R.: Searching for pheochromocytoma: a new and better test? Ann. Intern. Med., 123:150, 1995. 2. Ichikawa, T., Keyama, A,, Fujimoto, H., Henma, M., Saiga, T., Matsubara, N., Ozeki, Y. and Arimizu, N.: Retroperitoned ganglioneuroma extending across the medline: MR features. Clin. Imaging, 17:19, 1993.
Vol. 157, 1566-1568, May 1997 Printed in U.SA,
THEJOLWAL OF UROLOGY Copyright 0 1997 by h E R I c m UROLOCICAL kSSocl~TloS, INC.
CLINICAL EXPERIENCE WITH INCIDENTALLY DISCOVERED PHEOCHROMOCYTOMA AKIRA MIYAJIMA,* JUN NAKASHIMA, SHIRO BABA, MASAAKI TACHIBANA, KAORU NAKAMUM AND MAsARU M U M From the Department of Urology, Keio University School of Medicine, Shinjuku. Tokyo. Japan
ABSTRACT
Purpose: We reviewed 17 resected pheochromocytomas comprising 7 from symptomatic patients, and 10 unsuspected and incidentally discovered tumors. We compared various parameters concerning these 2 groups and investigated the features of the incidentally discovered pheochromocytoma. Materials and Methods: Patient gender and age, clinical symptoms and signs, tumor localization, detection methods, findings on imaging studies, urinary catecholamine concentrations, results of metoclopramide stimulation tests, treatments at operation and tumor size were evaluated. Furthermore, we compared the clinically diverse aspects arising between the symptomatic and incidentally discovered pheochromocytomas. Results: The 24-hour urinary noradrenaline and vanillylmandelic acid levels in the incidental cases tended to be lower than those in the symptomatic cases, while 24-hour urinary dopamine was significantly less (468 -C 221 compared t o 1,558 5 899 pg./day, respectively). Typical symptoms of pheochromocytoma were noted in 6 patients (60%) in the incidental tumor group. The incidental cases had a markedly high false-negative rate (71%) as noted by the metoclopramide stimulation test, although the symptomatic cases had a 100% positive rate. On the other hand, the average diameter of incidental tumors was significantly larger than that of the symptomatic lesions (55.5 -C 19.1 versus 35.9 -C 12.1 mm., respectively). Conclusions: Clinical signs and findings in patients with incidental tumors were weaker than those with symptomatic disease although most incidental tumors functioned. Lower urinary catecholamine values in the incidental tumors were consistent with these results. However, the surgical risk for incidental tumors was the same as that for symptomatic lesions. Therefore, patients with incidentally discovered pheochromocytomas scheduled to undergo surgery should be treated accordingly. KEY WORDS:pheochromocytoma, adrenal gland neoplasms, carcinoma
Advances in imaging diagnosis, high resolution ultrasonography, computerized tomography (CT) and magnetic resonance imaging (MRI) have resulted in a significant increase in incidentally discovered adrenal tumors, including pheochromocytoma.1.2 I t has been stated that a n adrenal tumor will be discovered incidentally for an unrelated reason in at least 2%'of patients undergoing abdominal CT and that the prevalence of pheochromocytoma in patients with a n incidentally discovered adrenal tumor should be approximately 6.5q.3 On the other hand, As0 and Homma reported a 2396 pheochromocytoma discovery rate for all incidentally discovered adrenal tumors in Japan.2 Thus, it is assumed that many incidentally discovered adrenal tumors may not be absolutely nonfunctioning.4 Identification of incidental pheochromocytomas among the hormonally active tumors is important from the viewpoint of perioperative treatment and the malignant potential. However, to our knowledge no clinical investigation has fully elucidated the characteristics of incidentally discovered pheochromocytomas. To evaluate the difference between the incidentally discovered and symptomatic pheochromocytomas we retrospectively reviewed 17 patients with pheochromocytomas who presented within the last 5 years.
MATERIALS AND METHODS
Incidentally discovered adrenal tumors were defined as those that were detected primarily during the course of an evaluation for a n unrelated disease or a routine physical examination. Therefore, this definition included previously unsuspected adrenal masses found a t any examination or during treatment even if the patient had symptoms or signs retrospectively caused by the adrenal tumor.2 Patients who presented with typical symptoms suspicious for a pheochromocytoma that was confirmed by examination were classified into the symptomatic group. Accordingly, we studied 10 incidental and 7 symptomatic pheochromocytomas that were surgically resected and pathologically diagnosed at our institute between 1991 and 1995. Case histories were reviewed for age at diagnosis; gender; presence of typical symptoms, including hypertension, headache and palpitation; findings on ultrasonography, CT, MRI and metaiodobenzylguanidine (MIBG) scans; result of a metoclopramide stimulation test; tumor localization; concentrations of 24-hour urinary catecholamine (adrenalin, noradrenalin and dopamine) and vanillylmandelic acid; preparation of adrenergic antagonist; intraoperative blood pressure elevation; operative blood loss; necessity for blood transfusion or dopamine infusion postoperatively; diameter of the surgical specimen, and pathological diagnosis. Data on 24-hour ~ r i Accepted for publication October 11, 1996. * Re uests for reprints: Department of Urology, National Defense nary catecholamine concentration, operative blood loss and MedicA College, 3-2, Namiki. Tokorozawa. Saitama 359, Japan. diameter of the surgical specimen were reported as mean 1566
CLINICAL EXPERIENCE WITH INCIDENTALLY DISCOVERED PHEOCHROMOCYTOMA
or minus standard deviation. Variables for different were compared using Student’s t test or the chisquare test. A level of p <0.05 was considered statistically significant. RESULTS
1567
toma. During the operation blood pressure was elevated in 5 symptomatic (71.4%) and 7 incidental (70%) cases. Baseline systolic and diastolic blood pressures were decreased in all cases with the vasodilator after resection of the tumors. Average blood loss during the operation was 488 2 389 gm. in the symptomatic and 740 2 798 gm.in the incidental groups (difference not significant). Blood t r a n s h i o n was necessary in 1 case in each group. In 3 symptomatic (42.9%) and 8 incidental (80%) cases blood pressure was maintained by continuous dopamine infusion after surgical excision. Mean diameter of the surgical specimen was 35.9 2 12.1 mm. in the symptomatic and 55.5 2 19.1 nun. in the incidental groups, which was significantly Merent. All tumors were pathologically diagnosed as pheochromocytomas.
The 3 men and 4 women with symptomatic tumors were 16 to 68 years old (mean age 41.4 2 14.7), and the 5 men and 5 women with incidental tumors were 37 to 69 years old (mean age 57.2 t 10.0). Accordingly, we believe that mean age in the symptomatic group is likely to be younger than that in the incidental group although the difference in our patients was not significant. Concerning clinical symptoms and signs, all symptomatic patients had typical hypertension related symptoms, while 6 with incidental disease (60%) presented with hypertension. Of these patients 3 had low grade fever DISCUSSION without typical symptoms and 1 was completely asymptomImprovements in imaging studies have resulted in an inatic. Five incidental pheochromocytomas were primarily found crease in incidentally discovered adrenal or retroperitoneal on CT and 5 on ultrasonography. These imaging studies were tumors. The prevalence of pheochromocytomas was reportdone mainly during routine annual physical examinations or edly 6.5%3 and this rate continues to increase. In our country for evaluation of unrelated diseases. Most incidental and the rate of incidentally discovered pheochmmocytomas has Symptomatic tumors were localized in the adrenal glands increased to more than 20% of all incidentally discovered except for 2 in the para-aortic area. AU cases were delineated adrenal tumors.2 Although unexpected adrenal tumors were by an iso-hypoechoicmass generated by ultrasonography and believed to be nonfbctioning endocrinologically, they actuby an iso-low density mass produced by CT. In most cases ally may not be nonfunctioning after all. These completely MRI demonstrated a low isointensity mass in the T1-weighted silent pheodmmocytomas are reportedly rare.6 Our incidenimage and a high intensity mass in the T2-weighted image. tally discovered pheochmmocytomas were mostly functionIn 1 incidental case the T1-weighted image denoted a high ing. Because of the dramatic symptoms functional tumorsare intensiti mass. MIBG scanning yielded 100 and 75% positive usually small when detected, whereas nonfunctional tumors rates in the symptomatic and incidental tumor groups, re- may be large.6 In our study the mean diameter of incidental tumors was also significantly larger than that of symptomspectively. The 24-hour urinary excretion of dopamine, adrenaline atic tumors. Crout and Sjoerdsma noted that pheochmmocyand noradrenaline was measured in all patients. Mean uri- tomas 50 gm.or larger are often asymptomatic because senary dopamine in the symptomatic tumors (1,558 2 899 pg. creted catecholamines are metabolized within the tumor.7 In daily) was significantly greater than that in the incidental contrast, tumors smaller than 50 gm. have slow turnover cases (468 5 221 pg. daily). No significant difference was rates and release fiee catecholamines into the circulation, observed in the mean values of adrenaline, noradrenaline exhibiting persistent symptoms and signs.8 The clinical diagnosis of pheochromocytoma is based on the and vanillylmandelic acid. Urinary dopamine levels were normal (316 to 1,272 pg. daily) in 3 symptomatic and all 10 subjective evaluation of signs and symptoms. When one enincidental tumors, and elevated in 4 symptomatic cases (p counters a patient with an incidentally discovered, possible <0.05). The 24-hour urinary noradrenalin levels were ele- pheochromocytomaone should carefully note the history and vated (more than 145 pg. daily) in all 7 symptomatic (1,527 ? perform a physical examination initially. Of our patients 1,467 pg. daily) and in 8 incidental (284 2 239 pg. daily) with incidentally discovered pheochmmocytomas 60% had tumors. This difference was not significant. If the borderline typical symptoms associated with the disease, consisting of was set at the 2-fold elevation of the upper limit then 6 of 7 hypertension, headache, palpitations and sweating attack, symptomatic (85.7%) compared to 2 of 10 incidental (20%) although 10%of patients were reported to be norm0tensive.Q tumors had more than a 2-fold elevated noradrenalin level The reasons for finding these normotensive patients despite and this difference was significant (p <0.05). There was no high circulating levels of catecholamines are reported to insignificant difference in urinary adrenaline and vanillylman- clude hypovolemia and nonresponsiveness due to prolonged delic acid values between the 2 groups. The results of the stimulation.7 Also multiple biochemical tests, including metoclopramide stimulation test were positive in 100 and plasma and %hour urinary catecholamine determinations, 29% of the symptomatic and incidental cases, respectively must be performed. Incidental tumors tend to exhibit lower 24hour urinary catecholamine values than symptomatic tu(skTS.cant difference, p <0.05). Hypertension was noted in 6 of 10 patients with incidental mors. Mean urinary dopamine was signhantly less in the tumors (see table). Preparation with an a-adrenergic antag- incidental than in the symptomatic cases, and the incidence onist or calcium channel blockers was done in all symptom- of positive urinary dopamine levels between the 2 groups was atic and 8 incidental cases, while a-adrenergic antagonists significantly different. All symptomatic and most incidental and calcium channel blockers were not used in the remaining tumors showed positive 24hour urinary noradrenaline lev2 incidental cases with no typical findings of pheochromocy- els, demonstrating high sensitivity (88.2%). However, significantly fewer incidental than symptomatic tumors had more than a 200% elevated noradrenaline level. These findings suggest that incidentally discovered pheochmmocytomas function despite the lower potential. When 1of these clinical Clinical symptom and signs in patients with pheochromocytoma and laboratory findings suggests pheochmmocytoma further No. Pheochmmocytonm evaluation should be performed.10 Particularly MRI can betSymptoms symptomatic Incidental ter delineate the tissue character and extent of the n m plasm,” and MIBG can be useful in determining the funcHypertension 6 6 tional character of a tumor and locating occult secondary or Headache 2 0 Fever 0 3 metastatic sites.8 Moreover, some provocation tests (metode None 0 1 pramide and glucagon) or a suppression teet (clonidine)
1568
CLINICAL EXPERIENCE WITH INCIDENTALLY DISCOVERED PHEOCHROMOCYTOMA
should be done. The metoclopramide stimulation test reportedly yields excellent specifkity.12 On the other hand, our incidental cases showed a high false-negative rate (71.4%) with the metoclopramide stimulation test and the possibility of a false-negative case (28.6%)with MIBG scanning. These results are likely to be produced by the low endocrinological potential of incidentally discovered pheochromocytomas, although functions exceeded the normal range. Indeed, we should integrate the results of various biochemical tests and diverse radiological studies into the diagnosis of a pheochromocytoma at this stage. If an incidentally discovered tumor is proved to be a functioning pheochmmocytoma, treatment should theoretically be the same as that for symptomatic disease. F'razosin, an a-adrenergicblocking agent, has been used preoperatively as an alternative to phenoxybenzamine at our institute. Pretreatment with padrenergic blockers is considered when arrhythmia or tachycardia becomes a problem. Intraoperativemanagement of these cases involves several concerns. Central vein pressure and arterial pressure monitoring should be used routinely to evaluate the hemodynamic parameters and cardiac function. Enflusane or isoflurane should be used for anesthesia because both decrease myocardid irritability.*3Intraoperative hypertension is believed to be treated with phentolamine or nitroprueside,and propanolo1 is excellent for the treatment of intraoperative supraventricular tachycardia, while patients with ventricular arrhythmias receive lidocaine. However, the use and regimen of these pharmacological agents vary with the administering institution. For persistent hypotension following tumor removal, volume replacement is required in conjunction with carefid cardiovascular monitoring. CONCLUSIONS
We suggest that retroperitoneal incidentally discovered tumors that cannot be ruled out as pheochromocytomas should be comprehensively evaluated. Incidentally discovered pheochromocytomas should also be treated prudently due to the inherent unpredictable risk.
DTPA-enhanced dynamic studies. Radiology, 171: 675, 1989. H.,Itaya, Y.,Suzuki, H., Kondo, K. and Saruta, T.: Meklopramide in the diagnosis of pheochromocytoma. Jap. Heart J., 26: 557, 1985. 13. Vaughan, E. D., Jr. and Blumenfeld, J. D.: The adrenals. In: Campbell's Urology, 6th ed.Edited by P. C. Walsh, A. B. Fktik, T. A. Stamey and E. D. Vaughan, Jr. Philadelphia: W. B. Saunders Co., vol. 3, chapt. 64,pp. 2360-2412, 1992.
12. Kawabe,
EDITORIAL COMMENT These interesting observations confirm the clinical dictum that patients with incidental adrenal masses should be evaluated to rule out pheochromocytoma (reference 3 in article). In large series of patients with clinically apparent pheochromocytomasthe most common clinical finding is hypertension, sustained or intermittent, which is found in 90 to 95% of cases (reference 13 in article). In contrast, of the 10 patients with incidental pheochromocytomas in this series only 60% presented with hypertension. Moreover, urinary catecholamine levels were also higher in the symptomatic patients. Urinary norepinephrine levels were elevated in 8 of the 10 patients with incidental lesions, although they were rarely (2 of 10) twice the normal level. It would appear that careful evaluation of epinephrine, norepinephrine and vanillylmandelic acid w i l l identify integrated hypersecretion of catecholamines in most patients with incidental lesions. Altbough not measured in this study, plasma catecholamine levels would be assumed to be less accurate in these normotensive patients. MRI showed the characteristic bright "2-weighted image in these patients and remains the appropriate imaging study for those with suspected pheochromoeytomas, symptomatic or incidental (reference 13 in article). The final and important point made by the authors is that these patients, although normotensive preoperatively, should still be expected to respond intraoperatively in a fashion similar to patients with symptomatic pheochromocytomas. Therefore, preoperative preparation with a-adrenergic antagonists or calcium channel blockera should be done in patients with incidental pheochmmocytomas. Moreover, the anesthesiologist should be fully prepared to respond with appropriate drugs in these patients just as they would in a patient with a symptomatic pheochromocytoma. E. Darracott Vaughan, Jr. Department of Urology New York HospitallCornell Medical Center New York,New York
REFERENCES
1. Gross, M. D. and Shapiro, B.: Clinical Review 50: clinically silent adrenal masses. J. Clin. Endow. Metab., 77: 885, 1993. 2. Aso, Y. and Homma, Y.: A survey on incidental adrenal tumors in Japan. J. Urol., 147: 1478, 1992. 3. Ross, N. S. and Aron, D. C.: Hormonal evaluation of the patient with a n incidentally discovered adrenal mass. New Engl. J. Med., 325: 1401, 1990. 4. Kobayashi, S.,s k i , T., Nonomura, K., Gotoh, T., Togashi, M. and Koyanagi, T.: Clinical experience of incidentally discovered adrenal tumor with particular reference to cortical function. J. Urol., 1M): 8, 1993. 5. Nagashima, F.,Hayashi, J., Araki,Y., Sugihara, T., Nomura, M., Morichika, Y., Inoue, J., Shibata, S. and Akagi, E.: Silent mixed ganglioneuroma/pheochromromocytomawhich produces a vasoactive intestinal polypeptide. Intern. Med., 32: 63,1993. 6. Whalen, R. K., Althausen, A. F. and Daniels, G. H.: Extraadrenal pheochromocytoma. J. Urol., 147: 1,1992. 7. Crout, J. R. and Sjoerdsma. A.: Turnover and metabolism of catecholamine in patients with pheochromocytoma. J. Clin. Invest., 4 3 94, 1964. 8. Bravo, E. L.: Pheochmocybma: new concepts and future trends. Kidney Int., 40:544, 1991. 9. Scott, H.W., Jr., Oates, J. A., Nies, A. S., Burko, H., Page, D. L. and Rhamey, R.K:Pheochromocytoma:present diagnosis and management. Ann. surg., 1sS:587, 1976. 10. Bravo, E. L. and Gif€ord, R. W., Jr.: Current concepts. Pheochromocytoma: diagnosis, localization and management. New Engl. J. Med., 311: 1298, 1984. 11. Krestin, G. P., Steinbrich, W. and Friedmann, G.: Adrenal masses: evaluation with fast gradientecho MR imaging and Gd-
REPLY BY AUTHORS
Our results demonstrate that urinary catecholamine levels in incidentally found cases were lower than those in symptomatic cases because of weak function. Accordingly, it can be surmised that the incidence of hypertension in incidentally discovered cases may be lower than that stated in the comment. However, 15 of our 17 cases (88%)had function, which is consistent with the 90 to 95% rate of hypertension noted. Mean values plus or minus standard deviation of plasma adrenaline, noradrenaline and dopamine in our series were 22.7 -t 59.7, 4.4 ? 5.6 and 0.7 ? 1.9 ngJml. in symptomatic cases and 0.4 2 0.7, 1.2 2 1.4 and 0 ng.1ml. in incidentally found cases (no significant difference). The limited sensitivity and specificity of plasma catecholamine for diagnosing pheochromocytoma have been well established.' MRI showed the characteristic bright T2-weighted image in our patients. It has also been reported that most neurogenic tumors are delineated brightly on T2-weighted images.2 Pheochromocytoma reportedly showed marked enhancement in the early phase on TIweighted images after the administration of gadolinium pentetic acid (reference 11 in article). Thus, in making the diagnosis of pheochromocytoma we integrated the results of various biochemical tests and diverse radiological studies a t this stage. 1. Krakoff, L. R.: Searching for pheochromocytoma: a new and better test? Ann. Intern. Med., 123:150, 1995. 2. Ichikawa, T., Keyama, A,, Fujimoto, H., Henma, M., Saiga, T., Matsubara, N., Ozeki, Y. and Arimizu, N.: Retroperitoned ganglioneuroma extending across the medline: MR features. Clin. Imaging, 17:19, 1993.