Case Report
A MALIGNANT ALDOSTERONOMA
Ann T. Sweeney, MD,1 Michael A. Blake, MRCPI, FFR(RCSI), FRCR,2 Leo S. Aish, MD,3 Vernon M. Pais, MD,4 John J. Dowling, MD,5 James C. Melby, MD,6 and George L. Tully III, MD, FACE1
ABSTRACT
Objective: To describe a case of primary aldosteron- ism due to an adrenocortical carcinoma (ACC) and high- light the need for thorough long-term follow-up.
Methods: We present the clinical, laboratory, radio- logic, and pathologic findings in a patient with ACC and review the related literature.
Results: A 52-year-old woman with a history of hypertension and hypokalemia was referred for evaluation of a 6-cm adrenal mass. Her biochemical studies revealed a serum aldosterone-to-renin ratio of 52 without evidence of cortisol, catecholamine, or androgen excess. She under- went surgical resection of this mass, and histologic analy- sis showed a focally brisk mitotic rate but no evidence of capsular or vascular invasion. In light of these findings, the biologic nature of the tumor was difficult to predict. Thus, it was thought to be an adrenocortical neoplasm. The patient underwent follow-up clinically, biochemical- ly, and with interval computed tomography. Nine years later, hypertension and hypokalemia redeveloped, and she was found to have metastatic ACC.
Conclusion: ACC can generally be reliably diag- nosed; however, in some cases, the true biologic behavior is difficult to predict. We emphasize the importance of careful clinical, biochemical, and radiologic surveillance in these difficult cases because surgical resection provides the best opportunity for cure in patients with adrenal cancer. (Endocr Pract. 2002;8:373-377)
From the 1Department of Medicine, Division of Endocrinology, 3Department of Pathology, 4Department of Surgery, and 5Department of Internal Medicine, St. Elizabeth’s Medical Center, Tufts University School of Medicine, 2Department of Radiology, Abdominal Imaging and Intervention Section, Massachusetts General Hospital, Harvard Medical School, and the ‘Endocrine Hypertension Unit, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts.
Address correspondence and reprint requests to Dr. A. T. Sweeney, Tufts University School of Medicine, Division of Endocrinology, St. Elizabeth’s Medical Center, CMP 5, 736 Cambridge Street, Boston, MA 02135. @ 2002 AACE.
Abbreviations:
ACC = adrenocortical carcinoma; CT = computed tomographic; DHEAS = dehydroepiandrosterone sul- fate; GRA = glucocorticoid-remediable aldosteronism; HPFs = high-power fields; HU = Hounsfield units; PAH = primary adrenal hyperplasia; VMA = vanillyl- mandelic acid
INTRODUCTION
Primary aldosteronism is due to the excessive elabo- ration of aldosterone independent or semi-independent of the renin-angiotensin system. Most cases result from either an aldosterone-producing adrenal adenoma or bilat- eral adrenal hyperplasia. We report an unusual case of a patient with hypertension, hypokalemia, and alkalosis who was found to have a pure aldosterone-producing adrenocortical neoplasm. The patient underwent follow- up, and almost a decade later, she was diagnosed with metastatic adrenocortical carcinoma (ACC). Generally, ACC can be reliably diagnosed; however, in some cases, the true biologic behavior is difficult to predict. We emphasize the importance of long-term follow-up in these difficult cases.
CASE REPORT
In 1991, a 52-year-old woman was referred for assessment of an incidental adrenal mass found during an evaluation for urinary urgency and microscopic hema- turia. She had a history of hypertension and hypokalemia and was being treated with a combination of triamterene and hydrochlorothiazide. She was also receiving conjugat- ed estrogens (Premarin). Her blood pressure was 160/110 mm Hg and heart rate was 80 beats/min; findings on phys- ical examination were otherwise normal. She had no signs of cortisol or androgen excess.
Laboratory studies revealed the following results (normal ranges are shown parenthetically): serum aldos- terone, 42 ng/dL (4 to 31); renin, 0.8 ng/ml per hour (0.4 to 8.8); potassium, 2.7 mEq/L (3.6 to 5.0); bicarbonate, 31 mEq/L (22 to 30); testosterone, 27 ng/dL (15 to 70); and dehydroepiandrosterone sulfate (DHEAS), 0.9 µg/mL (0
to 115). After a 1-mg dexamethasone suppression test, the AM plasma cortisol level was 5.0 µg/dL. Analysis of a 24-hour urine collection showed the following: metanephrines, 0.4 mg (normal, <1.3); vanillylmandelic acid (VMA), 5.5 mg (normal, 5 to 15); and free cate- cholamines, 50 µg (normal, 26 to 121). An abdominal computed tomographic (CT) scan performed without contrast enhancement revealed a 6- by 5-cm left adrenal mass with an attenuation value of 30 Hounsfield units (HU). The patient underwent an uncomplicated left adrenalectomy.
The gross pathology specimen was yellow and had focal areas of hemorrhage on the cut surface. It weighed 44 g and measured 8.0 by 6.5 by 5.5 cm. Histologically, the cells displayed a mixed alveolar and trabecular archi- tectural pattern. Nests of large lipid-rich cells, with numer- ous clear vacuoles, showed mild nuclear atypia and promi- nent nucleoli. Other cells had compact eosinophilic cyto- plasm with nuclear pleomorphism and prominent nuclei (Fig. 1). Although the mitotic rate was focally brisk-up to 4 per 50 high-power fields (HPFs)-there was no evidence of vascular invasion. These findings were thought to be consistent with an adrenocortical neoplasm.
Postoperatively, the patient had normal blood pres- sure and normokalemia. Her serum renin and aldosterone levels normalized at 1.5 ng/mL per hour and 3.7 ng/dL, respectively. Follow-up assessments included clinical examinations, biochemical studies, and serial abdominal CT scans. She remained normotensive until December 2000, when hypertension and hypokalemia redeveloped. Subsequently, therapy was initiated with valsartan to con- trol her blood pressure. Repeated serum renin and aldos- terone levels were 0.8 ng/ml per hour and 12 ng/dL, respectively. An abdominal CT scan revealed a 3- by 3- by 2-cm left suprarenal mass (Fig. 2), which was new in com- parison with findings on a previous scan in 1995. This scan also revealed a 10-mm right middle lobe lung nodule that had not been evident on prior studies.
The patient was admitted to the surgical service and underwent a right middle lobe wedge resection. The pathologic features were consistent with metastatic ACC (Fig. 3 A). Laboratory results included a serum aldos- terone level of <3 ng/dL, a testosterone value of 16 ng/dL, and DHEAS of 1.0 µg/mL. A 24-hour urine specimen showed the following: metanephrines, 0.2 mg; total cate- cholamines, 69 µg; VMA, 5.6 mg; 17-ketosteroids, 8.2 mg (normal, 5 to 15); tetrahydrodeoxycorticosterone, 42 µg (normal, 5 to 50); tetrahydroaldosterone, 12.9 µg (normal, 15 to 50); and urine free cortisol, 57.1 µg (normal, 10 to 50). She then underwent surgical exploration, which revealed a left suprarenal tumor that, on palpation, appeared to be invading the upper pole of the left kidney. The tumor was completely excised, along with the upper pole of the left kidney. On gross examination, the tumor specimen was fragmented, measuring 4.0 by 3.7 by 2.8 cm and 4.0 by 3.5 by 1.5 cm. On microscopic examination, the tumor extended to the apparent surgical margins, and there was evidence of angiolymphatic invasion. The tumor had more distinct nuclear pleomorphism than the lung nodule and previous left adrenal tumor but was otherwise histologically identical (Fig. 3 B).
The patient did well postoperatively, and her hypokalemia resolved. She has remained normotensive and in good health. This case was reviewed with the con- sulting oncologist, who thought that subjecting the patient to the unproven clinical efficacy and high toxicity of chemotherapeutic agents seemed unwarranted when she was doing so well clinically. She is being closely moni- tored clinically, biochemically, and with serial CT scans every 6 months. Her most recent CT scan, obtained 1 year postoperatively, revealed no recurrent masses.
DISCUSSION
The evaluation of an incidentally discovered adrenal mass involves focusing the history and physical examina-
DEWY 30.0cm
Pay
SIND
512
KY 120 HÀ 200
Large
A
-
B
tion on signs and symptoms of adrenal hyperfunction or malignant disease. Biochemical assessment should include a 24-hour urine collection for measurement of total catecholamines, VMA, and metanephrines, an overnight 1-mg dexamethasone suppression test, and plas- ma renin and aldosterone levels. On initial assessment, our patient had a 6-cm incidental adrenal mass in conjunction with hypertension, hypokalemia, and alkalosis-all highly suggestive of primary aldosteronism. Her ratio of serum aldosterone to renin was diagnostic at 52, and she had no biochemical or clinical evidence of catecholamine, corti- sol, or androgen excess.
Primary aldosteronism is a disorder due to the renin- independent overproduction of aldosterone. Classically, this oversecretion of aldosterone results in hypertension, hypokalemia, mild hypernatremia, and alkalosis (1). Most cases are due to an aldosterone-producing adenoma (Conn’s syndrome) or bilateral adrenal hyperplasia (idio- pathic hyperaldosteronism). Rare causes include an aldos- terone-producing adrenal carcinoma, unilateral primary adrenal hyperplasia (PAH), or glucocorticoid-remediable aldosteronism (GRA), each occurring with a frequency of 1%.
Primary aldosteronism should be suspected in all patients with hypertension who have spontaneous or easi- ly provoked hypokalemia. A serum aldosterone-to-renin ratio is a reliable screening test for primary aldosteronism (2-4). A ratio greater than 20 is highly suggestive of pri- mary aldosteronism, and a ratio that exceeds 50 is diag- nostic (5). The diagnosis rests on demonstrating aldos- terone excess in conjunction with a suppressed renin level. Salt loading may be performed to demonstrate inappropri- ate aldosterone secretion. Inappropriately increased serum aldosterone levels (>15 ng/dL) or urinary metabolites of aldosterone (tetrahydroaldosterone >50 µg/24 h) in the presence of a suppressed plasma renin level (<1 ng/ml per hour) are confirmatory. Once the diagnosis of hyperaldos- teronism has been confirmed, the cause must be deter- mined because the therapeutic approach differs consider-
ably depending on the nature of the lesion. Aldosterone- producing adenomas, aldosterone-producing ACCs, and PAH are treated surgically, whereas bilateral adrenal hyperplasia and GRA are treated medically. Bilateral adrenal venous sampling is the standard technique for dis- tinguishing an aldosterone-producing tumor from bilateral adrenal hyperplasia (6).
Certain imaging features are characteristic of a malig- nant lesion. ACC appears irregular in shape, is usually larger than 4 cm in diameter, has high unenhanced CT attenuation values (>20 HU), and may be of intermediate to high signal intensity on T2-weighted magnetic reso- nance imaging sequences (7). In contrast, the typical benign adenoma on an unenhanced CT scan is smooth, round, and homogeneous, measures less than 4 cm in diameter, and has a low density value (<10 HU). Our patient’s imaging characteristics, with a left adrenal mass of 6-cm diameter and an unenhanced attenuation value of 30 HU, were highly suggestive of ACC. As a result, wide resection in accordance with oncologic principles was per- formed, but annual follow-up with clinical, biochemical, and imaging studies should have been routine. Annual sur- veillance with imaging is very important and, in this case, would have led to the discovery of recurrent disease.
ACC is a rare aggressive disease with an estimated incidence of 1 case per 2 million people per year (8). The age at diagnosis varies from 6 months to 72 years (median age, 40 years) (9). There is a bimodal age distribution, with the first peak occurring before 5 years and the second during the fourth to fifth decades of life. A female pre- ponderance exists with a sex ratio of 2.5:1 (10). Most tumors are large; one study reported that 84% weighed more than 100 g (11). The clinical manifestation depends on whether the tumor is hyperfunctioning. Nonfunctioning ACCs commonly manifest with pain and an abdominal mass and usually have evidence of metastatic involvement at the time of detection.
Most ACCs are hyperfunctioning tumors (11). Cushing’s syndrome, occurring in isolation or with viriliz-
ing signs, is the most common initial clinical finding (11- 13). Estrogen-secreting ACCs are rare, accounting for 2% of hyperfunctioning tumors, and occur almost exclusively in male patients (14). Aldosterone-producing adrenal carcinomas are also quite rare and constitute 6% of hyperfunctioning tumors (15).
Histologic criteria for distinguishing benign from malignant adrenocortical neoplasms have been established (16). We have adopted the criteria outlined by Weiss (17) in a report of a series of 43 cases of adrenocortical neo- plasms. Nine histologic findings are associated with adrenocortical neoplasms that metastasize or recur locally: high nuclear grade, mitotic rate greater than 5 per 50 HPFs, atypical mitotic figures, eosinophilic tumor cell cytoplasm (>75% of tumor cells), diffuse architecture (>33% of tumor), necrosis, venous invasion, sinusoidal invasion, or capsular invasion. All 24 benign adenomas had two or fewer of these criteria, and 18 of 19 malignant tumors had four or more criteria. The system was modified so that the presence of three or more of these histologic findings predicts malignant behavior. The following three criteria were found exclusively in malignant tumors (never in the clinically benign tumors): mitotic rate greater than 5 per 50 HPFs, atypical mitotic figures, and venous inva- sion. Our patient’s initial histologic evaluation revealed none of these three criteria found only in malignant tumors and only two of the overall nine criteria-diffuse archi- tecture and an eosinophilic tumor cell cytoplasm. Nevertheless, the occurrence of metastatic ACC almost a decade later clearly establishes the malignant nature of her tumor.
In general, ACC can be reliably diagnosed; however, in some cases, the biologic nature of the tumor may be dif- ficult to predict (16). Weiss (17) reported 1 ACC that did not possess the minimal histologic criteria seen in the 18 other ACCs. Salassa et al (18) reported on a series of six tumors that were originally classified as ACC. On thor- ough pathologic review, four tumors had histologic fea- tures that were unequivocally malignant (19). The diagno- sis of ACC was equivocal in two small tumors. The patients with the unequivocally malignant tumors had a poor prognosis, whereas those with the equivocal patho- logic diagnosis were alive and well without biochemical or clinical evidence of recurrence 17 and 9 years, respec- tively, after surgical treatment. Ultimately, the clinical course may be the only factor that distinguishes a benign from a malignant tumor (20).
The diagnosis of ACC is associated with a grave prognosis. In a series of 105 patients with ACC, the medi- an duration of survival was 14.5 months (range, <1 to 175), and the 5-year survival was 22% (11). Survival was significantly lower for patients older than 40 years and with distant metastatic lesions at the time of diagnosis. No significant difference in survival was noted relative to sex, functional status, or weight of the tumor. Complete surgi- cal resection is the only effective and potentially curative therapy for ACC. In one study, the mean survival time in patients with unresectable tumors was 3 to 9 months (9).
In contrast, another study found that the mean survival time for patients undergoing complete surgical resection was 28 months, and the 5-year survival was 48% (8).
Our current patient’s presentation with pure hyperal- dosteronism is quite rare. Only nine other cases in the literature describe patients with pure hyperaldosteronism attributable to an ACC (21,22). The current case differs in that our patient’s recurrent disease was not associated with aldosterone excess. Her serum aldosterone level was 12 ng/dL and renin was 0.8 ng/ml per hour preoperatively during treatment with an angiotensin II receptor antago- nist. Ideally, the aldosterone level should exceed 15 ng/ml to demonstrate autonomous aldosterone secretion. This tumor did not seem to be overproducing deoxycorti- costerone, as evidenced by the normal 24-hour urinary tetrahydrodeoxycorticosterone excretion.
CONCLUSION
We describe a patient with hypertension and signs of mineralocorticoid excess who was found to have an adrenocortical neoplasm. The malignant nature of this tumor was not realized until almost a decade after her orig- inal diagnosis. We emphasize the importance of careful, long-term clinical, biochemical, and radiologic surveil- lance in these difficult cases, inasmuch as complete surgi- cal resection provides the best opportunity for cure in patients with adrenal cancer.
ACKNOWLEDGMENT
We thank Thomas Wilson of the Endocrine Hyperten- sion Unit, Boston University School of Medicine, for sharing his expertise in steroid chemistry.
REFERENCES
1. Conn JW. Primary aldosteronism, a new clinical syn- drome. J Clin Lab Med. 1955;45:6-15.
2. Young WF Jr, Hogan MJ, Klee GG, Grant CS, van Heerden JA. Primary aldosteronism: diagnosis and treat- ment. Mayo Clin Proc. 1990;65:96-110.
3. Hiramatsu K, Yamada T, Yukimura Y, et al. A screen- ing test to identify aldosterone-producing adenoma by measuring plasma renin activity: results in hypertensive patients. Arch Intern Med. 1981;141:1589-1593.
4. Weinberger MH, Fineberg NS. The diagnosis of primary aldosteronism and separation of two major subtypes. Arch Intern Med. 1993;153:2125-2129.
5. . Blumenfeld JD, Sealey JE, Schlussel Y, et al. Diagnosis and treatment of primary hyperaldosteronism. Ann Intern Med. 1994;121:877-885.
6. Melby JC, Spark RF, Dale SL, Egdahl RH, Kahn PC. Diagnosis and localization of aldosterone-producing ade- nomas by adrenal-vein catheterization. N Engl J Med. 1967;277:1050-1056.
7. McNicholas MM, Lee MJ, Mayo-Smith WW, Hahn PF, Boland GW, Mueller PR. An imaging algorithm for the differential diagnosis of adrenal adenomas and metastases. AJR Am J Roentgenol. 1995;165:1453-1459.
8. Stratakis CA, Chrousos GP. Adrenal cancer. Endocrinol Metab Clin North Am. 2000;29:15-25, vii-viii.
9. Pommier RF, Brennan MF. An eleven-year experience with adrenocortical carcinoma [with discussion]. Surgery. 1992;112:963-971.
10. Bertagna C, Orth DN. Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978). Am J Med. 1981;71:855-875.
11. Luton JP, Cerdas S, Billaud L, et al. Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy. N Engl J Med. 1990;322:1195-1201.
12. Schteingart DE, Oberman HA, Friedman BA, Conn JW. Adrenal cortical neoplasms producing Cushing’s syn- drome: a clinicopathologic study. Cancer. 1968;22:1005- 1013.
13. Freeman DA. Steroid hormone-producing tumors in man. Endocr Rev. 1986;7:204-220.
14. Henley DJ, van Heerden JA, Grant CS, Carney JA, Carpenter PC. Adrenal cortical carcinoma-a continuing challenge. Surgery. 1983;94:926-931.
15. Medeiros LJ, Weiss LM. New developments in the patho- logic diagnosis of adrenal cortical neoplasms: a review. Am J Clin Pathol. 1992;97:73-83.
16. Lack EE, Travis WD, Oertel JD. Adrenocortical neo- plasms. In: Lack EE, ed. Pathology of the Adrenal Glands. New York: Churchill Livingstone, 1990: 115-171.
17. Weiss LM. Comparative histologic study of 43 metasta- sizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984;8:163-169.
18. Salassa RM, Weeks RE, Northcutt RC, Carney JA. Primary aldosteronism and malignant adrenocortical neo- plasia. Trans Am Clin Climatol Assoc. 1975;86:163-172.
19. Lipsett MB, Hertz R, Ross GT. Clinical and pathologic aspects of adrenocortical carcinoma. Am J Med. 1963;35:374-383.
20. Slee PH, Schaberg A, Van Brummelen P. Carcinoma of the adrenal cortex causing primary hyperaldosteronism: a case report and review of the literature. Cancer. 1983;51:2341-2345.
21. Sakashita S, Kashiwagi A, Maru A, et al. Primary aldos- teronism due to adrenal cortical carcinoma. J Urol. 1984;132:959-961.
22. Greathouse DJ, McDermott MT, Kidd GS, Hofeldt FD. Pure primary hyperaldosteronism due to an adrenal cortical carcinoma. Am J Med. 1984;76:1132-1136.