Surgical management of aldosterone-producing adrenal adenomas

Surgical Management of Aldosterone-Producing Adrenal Adenomas A Review of 16 Patients

M. C. Theodore Mackett, MD, Loma Linda, California Milton G•.crane, MD, Lorna Linda, California Louis L. Smith,. MD, Loma Linda, California

Conn and Lewis [lJ first described a clinical syndrome associated with hypertension, hypokalemia, alk~losis and hyperaldosteronism over 25 years ago. ~hereafter, a primary and secondary form of the dIsease were defined and differentiated on the hasis of plasma renin activity, which is low in the primary form and high in the secondary form of hyperaldosteronism: Several types of prhnary hyperaldosteronism have been identified. These include aldos~erone-producing adenoma, idiopathic adrenocortICal hyperplasia, which may be glucocorticoid remedial or nonresponsive, and adrenocortical carci?oma. Causes of secondary hyperaldosteronism with Increased plasma renin activity include renal arterial stenosis, malignant hypertension, benign essential . hypertension, renin-secreting tumor and oral contraceptives .. . !viajor changes in the surgical management of pnmary aldosteronism have taken place since the disease was first described. Surgeons have come to recognize that primary hyperaldosteronism caused by adrenocortical hyperplasia responds poorly to adrenalectomy and is best treated by medical man~ agement. Patients most likely to benefit from adre~alectomy are those with an aldosterone-producing adenoma. Techniques have, therefore, evolved over the last 10 years to identify the patient with the ald?steronoma and to localize the lesion preoperatively WIth greater accuracy. Arte~iography has proved useful in patients with relatively large adrenal adenomas. More recently, adrenal venography and selective adrenal venous sampling of aldosterone have been widely employed in lateralizing the adenoma. Quadric analysis has been helpful in some centers in differentiating adenoma and hyperplasia; radiocholesterol scanning has served to localize even the ~rom the Department 01 Surgery, Loma Linda University, Loma Linda, Cal-

Ifornia. Requests lor reprints should be addressed to Theodore Mackett MD Department of Surgery, Loma Linda, California 92350. ., Presented at the 52nd Annual Meeting of the Pacific Coast Surgical AsSOCiation, Coronado, California, February 15-18, 1981.

Volume 142, July 1981

smaller lesions. Computed tomography and ultrasonography have come to occupy an adjunctive role . in the confirmation of venography and selective venous aldosterone sampling.

Clinical Material Sixtee~ patients underwent adrenalectomy for primary aldosteronism caused by an aldosterone-producing adenoma from 1968 to 1980 at Lorna Linda University Medical Center (Table I). The d,iagnosis of primary aldosteronism was confirmed in every patient by the determination of an elevated serum aldosterone level or increased adrenal venous aldosterone levels. All patients had decreased plasma renin activity. Preoperative localization was made in all patients by means of arteriography or venography, or by selective adrenal venous aldosterone sampling. The three most recently treated patients had computed tomographic studies which confirmed the IOClltion of the adenoma. These 16 patients included an equal number of men and women. The patients were aged 33 to 67 years, with a mean age of about 50 years. All patients had moderate hypertension, with systolic blood pressure ranging from 140 to 250 mm Hg, and diastolic blood pressure from 90 to 140 mm Hg. One patient had a 20 year history of high blood pressure, and most patients had a 2 to 15 year history of poorly controlled hypertension in spite of many varied medical regimens. Only one patient had no known history of hypertension and no physical complaints. He was referred for evaluation and treatment after a preemployment physical showed elevated blood pressure and subsequent laboratory studies demonstrated marked hypokalemia. The most common presenting complaints were headaches, generalized weakness, chronic fatigue, polyuria, polydipsia and dizziness. One patient had had several syncopal episodes. Another patient had had chest pain on physical exertion, thought to be angina, although there was no objective evidence 'of ischemic changes on electrocardiography. All patients demonstrated hypokalemic alkalosis of varying severity. All of these patients had a recorded serum potassium level of 1.4 to 3.2 mEq/liter (normal 3.4 to 4.5). With preoperative potassium replacement, aldosterone blocking with spironolactone and dietary sodium restriction, all patients showed a rapid return to normokalemic values. Most of their symptoms cleared dramatically.

89

',c

CD

.0

UI c

2-

!!.

3

c

0

Co

~

n D>

~

CD

,.3

:r

-4

<0 0

Headache, weakness, polyuria, polydipsia, paresthesia 'Weakness, paralysis Headache, weakness, dizziness, nocturia, paresthesia Headache, weakness, epistasis, syncope, paresthesia Headache Headache Nocturia, polyuria, polydipsia Headache, polyuria

180/120 (18 yr)

180/110 (2 yr)

210/130 (6 yr) 200/140 (9 yr)

240/140 (15 yr)

150/90 (15 yr)

152/110

245/120 (6 yr)

5

6

7 8

9

10

11

12

210/136 (7 yr) 2.6

3.3 3.2 1.9

2.7

<3

1.4

3.2

2.3 <3

1.8

2.2

<3

<3

2.7

2.9

Increased on left

Increased on left

Increased on left Increased on . right

Increased on left

Increased on right

Increased on left

Increased on • left'

• Normal 230 to 1 i 100 below age 40 years; 180 to 930 over age 40.

16

220/120 (2 yr) 140/90 (13 yr) 180/130

weakness, fatigue Headache, weakness Weakness. Headache, nocturia

180/120 (3 yr)

4

13 14 15

Headache

240/120 (13 yr)

3

Headache, weakness dizziness nocturia Headache" weakness, dizziness Headache, dizziness, paresthesia

Symptoms

250/120 (16 yr)

210/110 (20 yr)

Hypertension (mmHg)

Selective Serum Adrenal Vein Potassium Aldosterone (mEq/liter) level

150

140 85 87

,5 (resting), 42 (ambulatory)

160

10

10

10 25

10

65 (resting), 199 (ambulatory) 65 (resting), 280 (ambulatory)

220

50

10

Plasma Renin Activity(ng/h/l00 ml)

Venography equivocal

Venography Venography Venography

Venography

Venography

Venography

Venography equivocal Arteriography Venography, computed tomography Venography:

Arteriography

Venography

Venography, computed tomography Venography

Venography

Angiographic . localization

Patients With Aldosterone·Producing Adenomas Treated From 1968 to 1980

2

Patient

TABLE',

Posterior

Abdominal Abdominal. Posterior

Abdominal

Abdominal

Posterior

Abdominal

Abdominal Posterior

Posterior

Abdominal

Posterior

Abdominal

Posterior

Abdominal

Surgical Approach

left adenoma

left adenoma left adenoma left adenoma

Right adenoma. Multiple nodular

Right adenoma

Right adenoma

left adenoma

Right adenoma left adenoma

Right adenoma

Right adenoma

left adenoma

left adenoma

left adenoma

Right adenoma

Pathology

Normal

Persistent hypertension, poorly controlled on medication Normal Normal Normal; on medication

Normal

Normal

Normal

Normal Normal

Persistent hypertension, poorly controlled on medication Normal; on medication Normal; on medication Normal

Normal

Normal

Follow-Up Blood Pressure

~

!a

~

;t:;' (II

0

s::: III

Current Management of Aldosteronomas

MANAIEMENT PRIMARY

HYPE~LDOSTERONISM

LOW RENIN ACTIVITY P STIMULATION FAILURE ALDOSTiRONE SUPPRESSION

COMPUTERIZED TOMOGRAPHY VENOUS ALDOSTERONE SAMPLING RETROGRADE VENOGRAPHY

Figure 1. Algorithm lor the selection of patients for surgical treatment of primary aldosteIdiopathic ronlsm. I.H.A. adrenocortical hyperplasia; Rx treatment; • = total adrenalectomy on the side 01 localization and subtotal adrenalectomyon the contralateral side.

=

=

I

ADRENALECTOMY

Preoperative localization allowed a Young posterior approach adrenalectomy [2] in 8 of 16 patients. Most patIents undergoing posterior adrenalectomy were operated on after ,1973; after the introduction of adrenal venous sampling. However, in three patients adequate preoperative localization was realized with arteriography and venography, and the posterior approach was employed in these ' localized lesions as early as 1969. , Three of the eight patients who had transabdominai adrenalectomy underwent exploration for coexisting dis. ease. Two patients had possible evidence of renal arterial stenosis on preoperative arteriography and underwent concomitant renal arterial exploration. Another patient had severe reflux esophagitis, documented by appropriate preoperative studies, and underwent an antireflux proce.~ dure at the time of adrenalectomy., . Histologic study' of the adrenal gland confirmed the presence of a benign cortical adenoma consistent with aldosteronoma in all patients. The average hospital stay and the postoperative complication rate were essentially the same in the patients having the Young approach and those operated 0!l transabdominally. Three patients had postoperative urinary tract infections; two patients had a mild fever presumed to be secondary to atelectasis. There were no operative deaths, and no patient had acute postoperative adrenal insufficiency. Results The length offoUow-up is 3 months to 11 years in the 16 patients. One patient was normotensive and died from an unrelated cause 5 y~ars after removal o~ the adenoma. Nine patientS are symptom-free and normotensive without medication. Four patients are symptom-free but require antihyPertensive medication. ,Two patients remain refractory to all treat· ment regimens; one of these has essential hyperten-

Volume 142, July 1981

NO

ADENOMA + ALDOSTERONE

A

NOMA

/\

ALDOfTERONE BILATERAL

A~STERONE

UNILATERAL

I

I

I.H.A.

I

IlA.

MEDICAL

SURGICAL

Rx

Rx

..

sion with normal aldosterone levels and normal plasma renin activity on follow-up studies; the other is presumed to have renovascular hypertension due to severe diabetic vasculitis. Comments Primary aldosteronism caused by an aldosterone-producing adenoma is a surgically curable cause of hypertension. Unilateral adrenalectomy can be expected to have excellent results, and symptoms have been resolved in over 70 percent of patients having surgical removal of the adenoma [3]. Those patients not cured of hypertension are generally managed more easily by medical therapy. Our experience is essentially the same as that reported in the literature [4,5]. Follow-up evaluation of patients undergoing adrenalectomy for an aldosterone-producing adenoma at our hospital has not shown the high incidence of recurrence of hypertension reported by the Boston group [6]. The continuing challenge in the treatment of primary aldosteronism lies in the differentiation of aldosterone-producing adenoma from idiopathic adrenocortical hyperplasia. We have used an algo-rithm (Figure 1) based on biochemical and localization studies to select patients for surgical treatment. The diagnosis of primary aldosteronism' is first established by the presence of decreased plasma renin activity, elevated serum aldosterone levels and failure of aldosterone suppression. Adrenal venography and selective adrenal vein sampling follow. If an adenoma is demonstrated, the surgical exploration is performed. Recently, computed tomography has been

91

Mackett et al

Figure 2. Computed tomographic scan from a 67 year old woman with a Ie" adrenal adenoma, tHlst seen In the upper middle frame.

Figure 3. Computed tomographic scan from a 42 year old man with a Ie" adrenal adenoma, Identified by the marker.

used to confirm the location of an aldosterone-producing adenoma. We prefer the posterior approach for unilateral adrenalectomy. Other considerations must be ~iven to the differentiation of aldosterone-producing adenoma from idiopathic adrenocortical hyperplasia. The biochemical aberrations are generally more pronounced in the aldosterone-producing adenoma form of aldosteronism; hypokalemia is more severe and aldosterone levels more elevated, and adrenal venous sampling may show a higher aldosterone-cortisone

92

ratio. Quadric analysis of multiple variables including age, sex, hypertension, aldosterone secretion levels, serum potassium and plasma renin have been employed in some centers to differentiate these two forms of the disease [7]. We have not used either quadric or other forms of discriminant analysis to establish the diagnosis of aldosterone-producing adenoma in these cases. A high degree of resolution has been achieved with current localization techniques allowing the posterior approach to the involved adrenal. Selective adrenal

The American Journal 01 Surgery

Current Management of Aldosteronomas

Figure 4. Computed tomographic Bean from a 44 year old man with a Ie" adrenal adenoma, Identllled by the marker.

venous catheterization with sampling has been reliable in the diagnostic evaluation of patients with primary aldosteronism [8]. Problems of right adrenal vein catheterization have been reported; however, in our institution a greater than 75 percent incidence of right adrenal vein catheterization has been achieved. The left adrenal vein has been catheterized in nearly every case. One patient had adrenal hemorrhage at the time of venography, which was noted at the time of surgery. Deep vein thrombosis developed in another patient after catheterization of the femoral vein, requiring anticoagulant therapy before adrenalectomy. The use of computed tomography in diagnosing the cause of primary aldosteronism was recently reported [9]. This procedure appears to be a useful adjunct in the preoperative work-up of a patient suspected of having an aldosterone-producing adenoma. We have employed computed tomography in three patients and in each the tumor in question was clearly identified (Figures 2 to 4). Computed tomographic scanning has been recommended as the diagnostic study of choice in the initial evaluation of patients with primary aldosteronism, with venography and venous sampling reserved for those patients in whom no definite localization is found at the time of computed tomographic evaluation but in whom the biochemical findings strongly suggest aldosterone-producing adenomas. Computed tomography will undoubtedly play an ever-increasing role in the confirmation and localization of aldosterone-producing adenomas, and in the differentiation of these lesions from idiopathic adrenocortical hyperplasia. However, many adrenal aldosteronomas are small. In our series over half of the lesions were less than 1 em in diameter. Computed tomography does not yet

Volume 142, July 1981

provide accurate definition of these small lesions in all cases. We believe that selective venous sampling will continue to be useful in the localization of some adrenal lesions not clearly evident on computed tomographic scan. The preoperative preparation of patients undergoing adrenalectomy for aldosterone-producing adenomas includes correction of preexisting hypokalemia by oral potassium supplement, dietary sodium restriction and spironolactone administration. Unlike patients treated for pheochromocytoma, these patients are not hypovolemic; in fact, they are more likely volume-expanded. Intraoperative fluid requirements may, therefore, be smaller than in other types of adrenal surgery. Summary

Tabulation of the diagnostic evaluation and operative treatment of 16 patients with aldosteroneproducing adrenal adenomas is presented. The diagnosis of primary aldosteronism was confirmed in all patients by biochemical and radiologic studies. Selective venous sampling of adrenal vein aldosterone localized the adenoma in 14 patients and proved to be the single most helpful diagnostic procedure. Computed tomography was used recently to confirm the localization of these interesting lesions and may become the initial noninvasive diagnostic study. Confidence in the accuracy of preoperative localization has led to the choice of the posterior approach to the involved adrenal gland. Postoperative morbidity has been low regardless of the operative approach; however, subjective patient acceptance of posterior adrenalectomy suggests a more comfortable convalescence and a more rapid return to normal activity.

93

Mackett et al

References .1. Conn JW, Louis LA. Primary aldosteronism, a new clinical syndrome. J Lab Clln Med 1955;45:3-17. 2. Young HH. A technique for simultaneous exposure and operation on the adrenals. Surg Gynecol Obstet 1936;63: 179-88. 3. Oelarue NC, laidlaw JC, Kovacs K, Calaplnto R, Murrary FT. Hypertension due to "primary hyperaldosteronism"-surgical considerations. Surgery 1976;80:289-96. 4. Hunt TK, Schambelan M, Blgllerl EG. Selection of patients and operative approach In primary aldosteronism. Ann Surg

1975;182:353-61. 5. Auda SP, Brenna MF, Gill JR. Evolution of the surgical management of primary aldosteronism. Ann Surg 1980; 19 i: 1-7. 6. Egdahl RH. In discussion of Hunt TK, Schambelan M, Blgllerl EG. Selection of patients and operative approach In primary aldosteronism. Ann Surg 1975;182:353-61. 7. Aitchison J, Brown JJ, Ferris JB, et al. Quadric analysis In the preoperative distinction between patients with and without adrenocortical tumors In hypertension with aldosterone excess and low plasma renin. Am Heart J 1971;82:660-71. 8. Nlcolis GL; Milly HA, Modlinger RS, LJabriione JL. Percutaneous adrenal venography: a clinical study of 50 patients. Ann Intem Med 1972;76:889-909. 9. White EA, SChambelan M, Rust CR, Blgllerl, Muss AA, Korabkln M. Use of computed tomography In diagnosing the cause of primary aldosteronism. N Engl J Mad 1980;303:1503-1.

Discussion Orlo H. Clark (San Francisco, CA): The authors are to be congratulated for their clear presentation and careful evaluation of these 16 patients with aldosterone-producing adenomas. Their studies demonstrate (1) the wide variety of clinical manifestations; (2) that most, if not all, of these tumors can be localized preoperatively despite the fact that many are less than 1 cm in size; and (3) that virtually all patients benefit from removal of the adenoma since most patients become normotensive and the remainder are easier to manage with antihypertensive medications. The surgical management of patients with aldosterone-producing adrenal adenomas can be classified into five categories: (1) diagnosis, (2) preoperative localization, (3) preoperative preparation, (4) operative approach and treatment, and (5) postoperative care, early and late. The diagnosis is made, as in this study, in patients with hypertension, weakness, polydipsia, polyurea, especially nocturnal polyurea, headaches, fatigue, paresthesia and other symptoms. Laboratory tests may reveal unprovoked hypokalemia, proteinuria and alkalosis. Elevated plasma or urinary aldosterone levels and elevated 17-hydroxycorticosterone with suppressed plasma renin activity confirm the diagnosis. To diagnose patients with milder forms of primary hyperaldosteronism it is important to evaluate the suppressibility of plasma aldosterone after saline loading and the ability of plasma renin activity to be stimulated by a low sodium diet, furosemide and upright posture. Increased plasma aldosterone levels are found in patients with essential or malignant hypertension who are treated with diuretics, but plasma renin activity is also increased. These patients can therefore be eliminated from further consideration. A more difficult problem for the clinician is the differentiation of patients with aldosterone-producing adenomas and patients with idiopathic' hyperaldosteronism due to bilateral adrenal hyperplasia. This distinction is important because virtually all patients with adenomas benefit from operation, whereas most patients with hyperplasia do not.

94

Three methods used to determine whether a p.atient has an adenoma or bilateral hyperplasia are (1) quadric analysis, (2) the effect of posture on plasma aldosterone levels, and (3) the effect of angiotensin II on plasma aldosterone levels. Quadric an,alysis has been used by some groups, as mentioned by the authors, making use of the more severe metabolic changes in patients with aldosterone-producing adenomas than in patients with hyperplasia. Plasma aldosterone levels during sustained erect posture, after baseline morning plasma aldosterone levels, increase in patients with hyperplasia and usually decrease or remain the same in patients with adenoma. Infusion of angiotensin II results i~ a significantly higher increase in plasma aldosterone level in patients with idiopathic hyperplasia than in patients with adenoma. Also, the threshold dose of angiotensin II in patients with bilateral hyperplasia is considerably lower (0.3 ng/kg·min) than in patients with aldosterone-producing adenomas (1.0 ng/kg.min). Localization tests include noninvasive studies (ultrasonography, adrenal scintigraphy [iodine-131-19-iodocholesterol scanning] and computed tomographic scanning) and invasive studies (adrenal arteriography and venography with selective catheterization of adrenal veins for aldosterone levels). Of the noninvasive studies, computed tomographic scanning or iodocholesterol scanning are the most accurate with resolution of approximately 1.0 to 1.5 cm. Remember that many of these tumors are less than 1 cm in size. Dexamethasone suppression improves the accuracy of iodocholesterol scans and helps distinguish patients with bilateral nodular hyperplasia from those with solitary adenomas. Positive localization tests not only help in identifying the adenoma but also generally help rule out bilateral hyperplasia. At the University of California, San Francisco, computed tomographic scanning localized adenomas in 12 of 16 patients (75 percent). Adrenal venous sampling by a skilled angiographer is the most accurate and definitive method of diagnosing an aldosterone-producing adenoma, but is not without potential risks. Preoperative preparation includes correction of hypokalemia and hypertension, usually with spironolactone, an aldosterone antagonist. Potassium repletion, up to 6 to 8 g of potassium chloride/day, and sodium restriction are occasionally required. We use the same operative approach as reported by the authors, that is, a posterior approach with resection of the 12th rib, as described by Young. Two surgical considerations are that total adrenalectomy is recommended on the side of the adenoma because unilateral adrenal hyperplasia may coexist in a patient with an aldosterone-producing adenoma. Technically it is easier if one initially leaves the adrenal attached to the kidney while the most cephalad attachments of the adrenal gland to the diaphragm are divided. Postoperatively, patients who were prepared with spironolactone preoperatively are given saline solution as indicated by their condition. As stressed by the 'authors, these patients are not hypovolemic. Cortisol replacement is rarely necessary. Follow-up evaluation is important because hypertension may recur in some patients. I have several questions: (1) Do you now use salt loading to evaluate the suppressibility of plasma aldosterone and salt depletion to see ,whether serum renin levels can be stimulated in patients possibly having primary hyperaldosteron.ism? As many as 25 percent of patients may remain undiagnosed without using these procedures. (2) What was the smallest tumor identified by arteriography?

The American Journal of Surgery

Current Management of Aldosteronomas

(3) If you had primary hyperaldosteronism with biochemical data suggesting a unilateral tumor, wouldn't you rather have a computed tomographic scan or radioiodinated iodocholesterol scan with dexamethasone suppression of the adrenals rather than venography and adrenal vein catheterization with its potential complications? Richard Donald Sloop (Salem, OR): The authors emphasize the importance, once the diagnosis of primary aldosteronism has been made, of determining whether the source is an adenoma or hyperplasia, and ifit is adenoma, of demonstrating which. adrenal gland is involved. I would like to share an experience using an alternative method of answering these questions. We have utilized radionuclide imaging, using the second generation steroid metabolite iodomethyl cholesterol, so-called NP-59. This radionuclide image vividly demonstrates and lateralizes a 2 em aldosteronoma. The magnitude of the "hot spot" together with the very faint visualization of the remaining adrenal tissue should eliminate concern that the patient might have hyperplasia. In this noninvasive maneuver, both the presumed histologic diagnosis and lateralization of the tumor have been achieved. This study costs $260 plus the necessary Decadron® to suppress adrenal function. In our institution, a selective venous catheterization study costs $500 plus the laboratory determinations for hormone analysis. A computed tomographic study costs $226. Computed tomography does give good lateralization, but I wonder if it gives adequate assurance as to exactly what the histologic diagnosis will be. Hilding H. Olson (Seattle, WA): We reviewed 51 cases of medullary lesions at our hospital in Seattle, and we plan to present our findings at a later date. We have also re-

Volume 142, July 1981

sected several aldosterone-producing tumors. Last year we saw a lesion that I never had seen before. Have the authors or anyone in this audience had any experience with "black adenoma" of the adrenal cortex? Our patient had a fairly good response to removal of the left adreI1al and the contained tumor. Has anyone determined whether any endocrine function is assigned to this lesion? It seems to be rare, and very little has been published regarding its possible function. Louis L. Smith (closing): Dr. Clark rightfully emphasizes noninvasive studies, and we tertainly agree that these should be done first. We have followed the policy of doing total adrenalectomy on the involved side because of the problem of multiple adenomas. Regarding the size of afdosteromas that have been demonstrated by arteriography, we have suspected lesions of approximately 8 to 10 mm in size. In regard to salt loading and salt depletion, these have been done in selective cases to get a more accurate assessment of aldosterone secretion. Dr. Clark asked whether or not we do venography routinely, and the answer is no. We prefer to have the computed tomographic scan after preliminary biochemical studies are completed and then if there is any question on the scan, we obtain selective adrenal vein samples for aldosterone. Dr. Sloop, we have not performed radionucleotide imaging. In reviewing the literature, I get the impression that this type of study is associated with considerable error. Finally, Dr. Olson asked about "black adenomas." I don't think I can answer his question except to say that one woman in our series had a "black adenoma." It was an aldosterone-secreting tumor, and the reason for the pigmentation is not clear:

95