A Dangerous Liaison-Pheochromocytoma in Patients with Malignant Disease
Dirk Weismann,1 Martin Fassnacht,1 Barbara Schubert,2 Roland Bonfig,3 Alexander Tschammler,4 Stephan Timm,5 Stephanie Hahner, Christian Wunder,6 and Bruno Allolio1
1Endocrine and Diabetes Unit, Department of Medicine, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany
2Department of Dermatology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080, Wuerzburg, Germany 3Department of Urology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080, Wuerzburg, Germany 4Department of Radiology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080, Wuerzburg, Germany
5Department of General Surgery, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080, Wuerzburg, Germany “Department of Anaesthesia, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080, Wuerzburg, Germany
Background: Adrenal masses in patients with known malignancy may be interpreted as metastasized disease, although a significant proportion of these tumors are of adrenal origin. Despite improved imaging techniques, it remains difficult to distinguish an adrenal metastasis from a pheochromocytoma or a lipid-poor adrenocortical adenoma.
Patients and methods: We report a case series of four patients with established or suspected malignant disease (melanoma, transitional cell carcinoma and prostate carcinoma, thyroid carcinoma, colorectal carcinoma) harboring an adrenal mass. None of these patients showed clinical symptoms indicative for a pheochromocytoma.
Results: Surgery unrelated to the adrenal lesion (n = 3) or biopsy of the adrenal mass (n = 1) was performed without prior endocrine work-up. Pronounced hemodynamic insta- bility including hypertensive crisis was observed during surgery in all patients. In contrast, in the same patients preoperative «-blockade with phenoxybenzamine and an increased aware- ness of the potential risks led to improved hemodynamic stability following adrenalectomy for pheochromocytoma.
Conclusion: Our series is a strong reminder of the risks associated with surgery in patients harboring an unsuspected pheochromocytoma and underscores the need to exclude a pheo- chromocytoma in all patients with an adrenal mass and without a definitive diagnosis of the mass, especially when they are scheduled for surgery or adrenal biopsy. Otherwise, life- threatening hypertensive crisis can be precipitated even in the previously asymptomatic pa- tient.
Key Words: Pheochromocytoma-Adrenal biopsy-Adrenal mass-Adrenalectomy-Hyper- tensive crisis.
In patients with a known malignancy an adre- nal pheochromocytoma is often misinterpreted as
metastasis. Even if asymptomatic, these patients are at high risk of life-threatening hypertensive crisis during surgery.
Adrenal tumors belong to the most frequent types of human neoplasias. Although most of these tu- mors are benign adrenal adenomas, the adrenal gland is also a frequent site for metastasis. On total, only 19% of incidentally detected adrenal tumors are
metastases.1 But the likelihood of an adrenal tumor to be a metastasis is clearly increased in patients with a known malignant disease, particularly in patients with lung cancer or melanoma, which fre- quently metastasize to the adrenal gland. However, even in patients with lung cancer 25% of adrenal masses are benign adrenal lesions.2 As up to 8% of incidentally detected adrenal masses are pheochro- mocytomas, it is therefore likely that a significant proportion of adrenal masses in patients with malignant disease consists of catecholamine-secret- ing tumors. While imaging procedures are very helpful to differentiate lipid-rich adrenocortical adenomas from adrenal metastases,3 it is well known that pheochromocytomas closely resemble malignant adrenal lesions in computed tomography (CT) or magnetic resonance imaging (MRI). Thus, in known malignant disease a lipid-poor adrenal lesion is often assumed to represent metastasized disease and no further diagnostic efforts are made to rule out a pheochromocytoma.
We here report a case series of four patients with established or suspected malignant disease and adrenal masses. Surgery unrelated to the adrenal le- sion (n = 3) or biopsy of the adrenal mass (n = 1) was performed without prior diagnostic work-up for pheochromocytoma thereby creating a serious risk for the patients.
PATIENTS AND METHODS
Case 1
A normotensive 69-year-old man suffering from both a transitional cell carcinoma and a prostate carcinoma (T1 and T2, respectively) had an adrenal mass (diameter 3.8 cm), which was assumed to be a metastasis based on its appearance in CT. The patient did not report any symptoms suggestive for a pheo- chromocytoma. A radical cystoprostatectomy with pelvine lymphadenectomy was performed and an ileo-cecal bladder substitution was formed. During surgery, systolic blood pressure repeatedly rose to >300 mmHg requiring multiple injections of urapidil followed by a prolonged phase of hypotension requiring treatment with norepinephrine (Fig. 1). A pheochromocytoma was confirmed after surgery by elevated urinary catecholamine excretion (Table 2) and a positive I123-MIBG scintigraphy. After preop- erative treatment with phenoxybenzamine (maximum dose: 60 mg/day) and bisoprolol, a right-sided open adrenalectomy and urethrectomy was performed
safely in a second surgical approach with a maximum systolic blood pressure of 170 mmHg (Fig. 1). Pathohistological examination confirmed the diag- nosis of a pheochromocytoma.
Case 2
A 70-year-old man with colorectal carcinoma (T2) and bilateral adrenal masses (maximum diameter 3.2 cm) without clinical evidence of endocrine activity underwent left-sided hemicolectomy for removal of the stenosing tumor. During surgery, systolic blood pressure repeatedly increased from 120 to 210 mmHg and was controlled only after multiple injections of urapidil.
Investigation after surgery revealed a pheochro- mocytoma with elevated urinary catecholamine excretion (Table 2) and a high uptake of I123-MIBG in projection of the left adrenal tumor. The tumor in the right adrenal demonstrated high fat content in chemcial-shift MRI consistent with an adenoma and the further endocrine work-up was unremarkable (Table 2). Preoperative treatment with increasing doses of phenoxybenzamine (maximum dose: 30 mg/ day) was begun and a left-sided transabdominal adrenalectomy was accomplished without complica- tions. Maximum systolic blood pressure during sur- gery was 170 mmHg (Fig. 1). Pathohistological examination confirmed the diagnosis of a pheochro- mocytoma and the appearance of the right adrenal remained unchanged during follow-up.
Case 3
A 52-year-old man with goitre and cold nodules in thyroid scintigraphy was admitted for thyroidectomy because of suspicious fine-needle aspiration cytology. An abdominal ultrasound examination before sur- gery revealed bilateral adrenal masses (3.5 and 3.0 cm, respectively) but thyroid surgery was per- formed without any further endocrine investigation. Calcitonin was 3.7 pmol/L (<3.2) preoperatively.
During surgery systolic blood pressure rose to >360 mmHg. Pathohistological examination of the
c
FIG. 1. Hemodynamic profiles are shown for operations for neo- plastic diseases (left panel) prior adrenalectomy for pheochromo- cytoma (right panel). Black arrows show administration of antihypertensive drugs and red bars indicate administration of vasopressors. Hypertensive episodes were not only triggered by manipulation in the vicinity of the tumor (cases 1 and 2, left panel), catecholamine release could also be precipitated by other events during anesthesia and surgery (e.g., induction of anesthesia, intu- bation of the trachea and removal of the tracheal tube; case 3, left panel).
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| Patient | Age (years) | Neoplasias additional to adrenal lesions | Blood pressure and heart rate |
|---|---|---|---|
| Case 1 | 69 | Prostate cancer, | 120/70 mmHg |
| transitional cell carcinoma | 84 bpm | ||
| Case 2 | 70 | Colon cancer | 120/50 mmHg 74 bpm |
| Case 3 | 52 | Nodular goitre with suspected | 135/87 mmHg |
| thyroid carcinoma | 84 bpm | ||
| Case 4 | 50 | History of melanoma | 130/80 mmHg |
| 70 bpm |
None of the patients were taking any antihypertensive drug before the first operation.
| Patient | Urinary catecholamine excretion | Cortisol nmol/ 24 h (µg/24 h) | ||||
|---|---|---|---|---|---|---|
| Epinephrine nmol/24 h (µg/24 h) | Norepi- nephrine nmol/24 h (µg/24 h) | Meta- nephrine mmol/24 h (mg/24 h) | Normeta- nephrine mmol/24 h (mg/24 h) | Dexamethasone suppression test nmol/l (µg/dl) | ||
| Case 1 | 194.7 (33) | 743.4 (126) | 9,096 (1,794) | 11,550 (2,278) | 60.7 (2.2)* | |
| Case 2 | 418.9 (71) | 365.8 (62) | 14,730 (2,905) | 2,200 (434) | 102 (3.7)* | 254.7 (9.23) |
| Case 3 | 690.3 (117) | 3,976.6 (674) | 11,422 (2,253) | 16,381 (3,231) | 93.8 (3.4) *** | |
| Case 4 | 879.1 (149) | 619.5 (105) | 7,503 (1,480) | 3,676 (725) | <27.6 (<1.0) ** | 833.5-30.2 |
Normal values for urinary epinephrine, norepinephrine and metanephrine (and normetanephrine) excretion are <118 nmol/24 h (20 µg/ 24 h), <619.5 nmol/24 h (105 µg/24 h) and <1622 mmol/24 h (320 µg/24 h), respectively. Dexamethasone suppression test was performed with 1 mg (*), 2 mg ( ** ) or 3 mg ( *** ); normal values are <82.8 nmol/1 (3 µg/dl). Normal range for cortisol excretion in the urine is 276- 2,484 nmol/1 (10-90 µg/dl).
Plasma metanephrines were not routinely measured at the time of diagnosis in these four patients.
thyroid gland demonstrated adenomatous goitre with no evidence for a thyroid carcinoma or C-cell hyperplasia. The patient was admitted to our hospital for further investigation of the adrenal lesions. Uri- nary excretion of catecholamine metabolites was clearly increased (Table 2) and I123-MIBG-scintigra- phy demonstrated high uptake in the right adrenal mass with no accumulation of I123-MIBG elsewhere. The further endocrine work-up was unremarkable (Table 2) and the left lesion was suspected to be a hormonally inactive benign lesion according to its appearance in MRI studies. MEN II was excluded by mutational analysis of the RET-protooncogene. Therefore, right-sided unilateral laparoscopic adre- nalectomy was performed after pretreatment with phenoxybenzamine (up to a dose of 95 mg/day) without major hypertensive or hypotensive episodes. After a first postoperative visit the patient was lost to follow-up.
Case 4
A 50-year-old normotensive man was seen for a scheduled follow-up 10 years after excision of a superficial spreading melanoma. Routine abdominal
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ultrasound examination revealed a left-sided adrenal mass (5x 5 cm). Based on the assessment of CT scans, it was diagnosed as most likely malignant. Addition- ally, a CT scan of the thorax showed numerous small bilateral pulmonary nodules (<0.5 cm). To further establish the diagnosis of a metastasized melanoma a CT-assisted biopsy of the adrenal mass was performed
(Fig. 2). All melanoma-specific markers were nega- tive, but a definitive diagnosis could not be made based on the specimen. Only prior to a second biopsy a consultant endocrinologist was involved. He strongly recommended determination of urine cate- cholamine excretion prior to biopsy. Highly elevated urinary catecholamines (Table 2) established the diagnosis of a pheochromocytoma. An I123-MIBG scan was positive for the adrenal lesion, without evi- dence for pulmonary metastasis. After pretreatment with phenoxybenzamine (maximum dose 40 mg/day) a laparoscopic adrenalectomy was performed. The diagnosis was confirmed by histopathology.
During follow-up imaging (>4 years) the small pulmonary lesions remained unchanged.
DISCUSSION
Our series is a strong reminder that unsuspected pheochromocytoma is a potentially life-threatening disease. Pronounced hemodynamic instability including hypertensive crisis was observed in all our patients during surgery for neoplastic disease not related to the pheochromocytoma.
Platts et al.4 have reported that anesthesia and surgery were the cause of death in 16 out of 62 pa- tients with occult pheochromocytoma. In addition, Primhak has described sudden death after minor abdominal trauma in a patient with occult pheo- chromocytoma. However, in our series the adrenal lesions had been known before surgery and a diag- nostic work-up following generally accepted guide- lines6 9 would have established the diagnosis. Thus even in case of a known malignancy it is mandatory to rule out a pheochromocytoma in the presence of an adrenal tumor, particularly prior to surgical pro- cedures. As none of our patients had clinical symp- toms suggestive for catecholamine excess, the latter recommendation obviously holds true also for asymptomatic patients with an adrenal mass. For analysis, measuring the excretion of catecholamines and meta- and normetanephrines in a 24-h urine sample or measuring plasma metanephrines in a blood sample10 are both established methods, but repeated measurements (e.g., up to three times) are recommended to rule out a pheochromocytoma. In this series, all pheochromocytomas were visualized by MIBG-scintigraphy. But the sensitivity of MIBG- scintigraphy is only 80-90%11,12 and, therefore, it is not possible to exclude a pheochromocytoma by a negative MIBG-scintigraphy. Before an adrenal mass is removed surgically, a complete hormonal evalua-
| First surgery (n = 3) | Second surgery (n = 3) | |
|---|---|---|
| Maximum SAP, mmHgª | 295 ± 40 | 192 ± 20 |
| Minimum SAP, mmHgª | 80 ± 10 | 83 ± 6 |
| SAP > 200 mmHg, nº | 1 [1-4] | 0 [0-1] |
| Highest heart rate, bpmª | 115 ± 2 | 97 ± 5 |
| Lowest heart rate, bpmª | 53 ± 3 | 48 ± 6 |
ª Data presented as mean ± standard deviation.
b Number of episodes in a given patient, median with the range in parentheses.
SAP, systolic arterial pressure; bpm, beats per minute
tion is necessary including investigation of hyper- cortisolism in all patients and aldosterone excess in patients with hypertension or hypokalemia.13
Hemodynamic instability during surgery for pheochromocytoma is clearly higher than during surgery for adrenocortical tumors14 and is in most instances a result of sudden catecholamine release from the tumor. This is mainly caused by mechanical manipulation of the tumor, which may have occurred inadvertently in our patients, in particular in cases 1 and 2, as the pheochromocytoma was in the vicinity of the surgical area. However, catecholamine release can be precipitated also by other events during anesthesia and surgery like induction of anesthesia, intubation of the trachea and removal of the tracheal tube,15 which could have been the triggering factor for the hypertensive crisis at the end of the first sur- gery in patient 3 (Fig. 1, Table 3).
Another aspect contributing to high intraoperative instability during surgery in the presence of an unsuspected pheochromocytoma could be an inade- quate preparation for immediately treating sudden unsuspected hypertensive crisis. This immediate treatment is demonstrated by the hemodynamic profile of the adrenalectomy in case 3, where anti- hypertensive drugs were administrated immediately after an increment of systolic blood pressure, safely preventing a hypertensive episode with a systolic blood pressure >200 mmHg (Fig. 1).
Anaesthesia for pheochromocytoma follows established rules.15 Both «-blocking agents (e.g., urapidil) for hypertensive episodes and ß-blockers (e.g., esmolol) for tachycardia should be readily available during surgery for pheochromocytoma, whereas the use of these agents may be delayed, if pheochromocytoma is not suspected.
Moreover, to improve hemodynamic stability during surgery for pheochromocytoma, pretreatment with a-blocking agents or alternatively calcium
antagonists16 is generally recommended and is miss- ing, if a pheochromocytoma is not considered prior surgery.
In one of our cases biopsy of the pheochromocytoma was performed. While in this patient the biopsy was tolerated without major side effects, it may be associ- ated with hypertensive crisis and even death. 17,18 Thus biopsy of a pheochromocytoma is contraindicated and biopsy of a lipid-poor adrenal lesion before ruling out a pheochromocytoma is highly dangerous.
In summary, our series underscores the need to rule out a pheochromocytoma in all patients harboring an adrenal mass and without a definitive diagnosis of the mass, in particular in those scheduled for surgery or adrenal biopsy. Otherwise life-threatening hyperten- sive crisis may occur, even in the previously asymp- tomatic patient.
ACKNOWLEDGMENT
No financial assistance was received for this work.
REFERENCES
1. Mansmann G, Lau J, Balk E, Rothberg M, Miyachi Y, Bornstein SR. The clinically inapparent adrenal mass: Update in diagnosis and management. Endocr Rev 2004; 25:309-340.
2. Gillams A, Roberts CM, Shaw P, Spiro SG, Goldstraw P. The value of CT scanning and percutaneous fine needle aspiration of adrenal masses in biopsy-proven lung cancer. Clin Radiol 1992; 46:18-22.
3. Fassnacht M, Kenn W, Allolio B. Adrenal tumors: How to establish malignancy? J Endocrinol Invest 2004; 27:387-399.
4. Platts JK, Drew PJ, Harvey JN. Death from phaeochromo- cytoma: lessons from a post-mortem survey. J R Coll Physi- cians Lond 1995; 29:299-306.
5. Primhak RA, Spicer RD, Variend S. Sudden death after minor abdominal trauma: An unusual presentation of phaeochrom- ocytoma. Br Med J (Clin Res Ed) 1986; 292:95-96.
6. Ross NS, Aron DC. Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990; 323:1401-1405.
7. Kievit J, Haak HR. Diagnosis and treatment of adrenal inci- dentaloma. A cost-effectiveness analysis. Endocrinol Metab Clin North Am 2000; 29:69-90, viii-ix.
8. Grumbach MM, Biller BM, Braunstein GD, et al. Manage- ment of the clinically inapparent adrenal mass (“incidentalo- ma”). Ann Intern Med 2003; 138:424-429.
9. Lau J, Balk E, Rothberg M, et al. Management of clinically inapparent adrenal mass. Evid Rep Technol Assess (Summer) 200; 2:1-5.
10. Lenders JW, Pacak K, Walther MM, et al. Biochemical diag- nosis of pheochromocytoma: Which test is best? JAMA 2002; 287:1427-1434.
11. Guller U, Turek J, Eubanks S, Delong ER, Oertli D, Feldman JM. Detecting pheochromocytoma: defining the most sensitive test. Ann Surg 2006; 243:102-107.
12. Van Der Horst-Schrivers AN, Jager PL, Boezen HM, Schouten JP, Kema IP, Links TP. Iodine-123 metaiodobenzylguanidine scintigraphy in localising phaeochromocytomas-experience and meta-analysis. Anticancer Res 2006; 26:1599-1604.
13. Aron DC. The adrenal incidentaloma: Disease of modern technology and public health problem. Rev Endocr Metab Disord 2001; 2:335-342.
14. Weismann D, Fassnacht M, Weinberger F, et al. Intraopera- tive haemodynamic stability in patients with phaeochromocy- toma- minimally invasive versus conventional open surgery. Clin Endocrinol 2006; 65:352-358.
15. Kinney MA, Narr BJ, Warner MA. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesthes 2002; 16:359-369.
16. Proye C, Thevenin D, Cecat P, et al. Exclusive use of calcium channel blockers in preoperative and intraoperative control of pheochromocytomas: Hemodynamics and free catecholamine assays in ten consecutive patients. Surgery 1989; 106:1149-1154.
17. McCorkell SJ, Niles NL. Fine-needle aspiration of catechol- amine-producing adrenal masses: A possibly fatal mistake. AJR Am J Roentgenol 1985; 145:113-114.
18. Casola G, Nicolet V, van Sonnenberg E, et al. Unsuspected pheochromocytoma: Risk of blood-pressure alterations during percutaneous adrenal biopsy. Radiology 1986; 159:733-735.