CONCOMITANT SECRETION OF GLUCOCORTICOID, ANDROGENS, AND MINERALOCORTICOID BY AN ADRENOCORTICAL CARCINOMA: CASE REPORT AND REVIEW OF LITERATURE
Caroline K. Messer, MD,1 Alexander Kirschenbaum, MD,2 Maria I. New, MD,3 Pamela Unger, MD,4 J. Lester Gabrilove, MD, FACE,1 and Alice C. Levine, MD1
ABSTRACT
Objective: To present a case of concomitant secretion of cortisol, androgens, and 11-deoxycorticosterone (DOC) by an adrenocortical carcinoma and review the literature in an attempt to identify similar cases.
Methods: The patient’s medical history, physical examination, laboratory data, computed tomographic scan, and histopathologic results were analyzed and sum- marized in a case report, and an extensive review of the lit- erature was performed.
Results: Endocrinologic data showed excess cortisol production, substantially elevated testosterone and androstenedione levels, and profoundly increased DOC in the setting of suppressed aldosterone. An abdominal com- puted tomographic scan showed a left adrenal tumor. A left adrenalectomy was performed, and the histopatholog- ic diagnosis was stage II adrenocortical carcinoma. The review of the pertinent literature revealed the absence of any identical cases in the past.
Conclusion: Our patient presented with a rare case of cosecretion of cortisol, testosterone, androstenedione, and DOC by an adrenocortical carcinoma, resulting in a clini- cal picture consistent with Cushing’s syndrome, hyperan- drogenism, and primary hypermineralocorticoidism. We recommend the routine performance of a DOC assay in the setting of mineralocorticoid excess in association with low plasma aldosterone levels. (Endocr Pract. 2007;13: 408-412)
Abbreviations:
ACC = adrenocortical carcinomas; CT = computed tomographic; DOC = 11-deoxycorticosterone; HU = Hounsfield units
INTRODUCTION
Adrenocortical carcinomas (ACC) are rare neoplasms that occur in approximately 0.5 to 2 persons per 1 million patients yearly (1). Reportedly, these tumors have a bimodal distribution, with peak incidences before age 5 years and during the fourth and fifth decades of life (2). Women tend to have a preponderance of functioning tumors, whereas men are more likely to develop nonfunc- tioning tumors (3-5). Approximately 30% to 40% of adults with functional ACC present with Cushing’s syn- drome. Thus, hypercortisolism is the most commonly associated syndrome (6). In contrast, Cushing’s syndrome with concomitant virilization occurs in only 24% of patients with functional ACC. Virilization alone has been reported in 20% to 30% of patients with this type of can- cer (7). Feminization occurs in approximately 6% of cases, whereas hyperaldosteronism has been reported in only 2.5% of cases. There are very few reported cases of production of 11-deoxycorticosterone (DOC) by ACC causing mineralocorticoid hypertension, and none of these cases reported concurrent Cushing’s and virilization syn- dromes (8-14). We present a rare case of cosecretion of cortisol, testosterone, androstenedione, and DOC by an adrenocortical carcinoma, resulting in a clinical picture consistent with Cushing’s syndrome, hyperandrogenism, and primary hypermineralocorticoidism.
CASE REPORT
A 42-year-old woman with no significant past med- ical history was referred to our clinic with a 5-month his- tory of wheezing, an 18-kg weight gain, hypertension, difficulty climbing stairs, easy bruising, and mood swings. She also reported having 5 months of amenorrhea in the setting of previously normal menstrual cycles. On physi- cal examination, the patient had hypertension (blood pres- sure, 140/90 mm Hg). She had a cushingoid appearance with facial plethora, increased dorsoclavicular and supra- clavicular fat, hyperpigmented striae on her abdomen and upper thighs, appreciable central obesity, and wasting of her extremities. Of note, she had only mild facial hir- sutism, no acne, and no signs of virilization. Initial labo-
Submitted for publication July 21, 2006
Accepted for publication October 6, 2006
From the Departments of 1Internal Medicine (Endocrinology), 2Urology, 3Pediatrics, and 4Pathology, Mount Sinai School of Medicine, New York, New York.
Address correspondence and reprint requests to Dr. Caroline K. Messer, Department of Internal Medicine (Endocrinology), Mount Sinai School of Medicine, 1470 Madison Avenue, New York, NY 10029.
@ 2007 AACE.
ratory studies revealed hypokalemia, which persisted despite vigorous potassium supplementation.
Abnormal hormonal levels are noted in Table 1 and include elevated random serum, midnight salivary, and 24-hour urine cortisol levels in the setting of suppressed levels of adrenocorticotropic hormone (corticotropin). Her serum testosterone level was also substantially increased, with values in the high-normal male range. Her androstenedione level was more than twice the upper limit of normal, whereas her dehydroepiandrosterone sulfate and 17a-hydroxyprogesterone levels were not consider- ably elevated. Estradiol levels were in the follicular phase range, and serum gonadotropin levels (luteinizing hor- mone and follicle-stimulating hormone) were suppressed. Her plasma aldosterone level was decreased in conjunc- tion with a grossly elevated DOC level. She had normal
fasting glucose levels and hemoglobin A1c levels. Additionally, results of thyroid function tests, prolactin, urine metanephrines, and the hemogram were all within normal limits.
A computed tomographic (CT) scan of the abdomen demonstrated a large heterogeneous mass just anterior to the left kidney, most likely arising from the left adrenal gland, measuring 5.5 by 3.8 cm (Fig. 1). Its attenuation on noncontrast imaging (38 Hounsfield units [HU]) and its retention of contrast medium (67 HU at 70 seconds and 56 HU at 10 minutes) did not allow the lesion to be charac- terized as an adenoma (adrenal lesions with attenuation values of more than 10 HU on unenhanced CT or an enhancement washout of less than 50% and a delayed attenuation of more than 35 HU are suspicious for malig- nant involvement). On the basis of its heterogeneous
| Analyte | Before | After | Reference range |
|---|---|---|---|
| Sodium (mEq/L) | 146 | 139 | 135-146 |
| Potassium (mEq/L) | 2.3 | 4.2 | 3.5-5.1 |
| Blood urea nitrogen (mg/dL) | 8 | Not assessed | 7-25 |
| Creatinine (mg/dL) | 0.9 | Not assessed | 0.5-1.2 |
| Fasting glucose (mg/dL) | 78 | 112 | 65-115 |
| Hemoglobin A1c (%) | 6.3 | 6.3 | 4.1-6.5 |
| Cortisol | |||
| Free, 24-h urine (ug/L) | 134.9 | Not assessed | 10-110 |
| Serum (ug/dL) | 47.5 | 12.4 | 5-25 |
| Salivary (nmol/L) | 103.4 | Not assessed | <0.3-4.3 |
| Adrenocorticotropic hormone (pg/mL) | 2 | 14 | 9-52 |
| Luteinizing hormone, serum (mIU/mL) | 0.0 | Not assessed | 15-62+ |
| Follicle-stimulating hormone, serum (mIU/mL) | <0.7 | Not assessed | 20-138+ |
| Prolactin (ng/ml) | 6.0 | 8.8 | 2.8-29.2 |
| Estradiol (pg/mL) | 84 | Not assessed | <32 |
| Dehydroepiandrosterone sulfate (ug/dL) | 280 | <15 | 35-430 |
| Testosterone (ng/dL) | 672 | 12 | 14-76 |
| Androstenedione (ng/dL) | 853 | 22 | 47-268 |
| 17a-Hydroxyprogesterone (ng/dL) | 159.0 | <10 | 30-71¢ |
| 20-250§ | |||
| 11-Deoxycorticosterone (ng/dL) | 385 | 5.5 | 2-19 |
| Plasma aldosterone (ng/dL) | <1 | 3.5 | 1-16/ |
| Plasma renin activity (ng/mL/h) | 2.35 | Not assessed | 4.0-7.7 |
*Values outside the reference range are shown in boldface.
¡Normal menopausal.
Follicular phase.
§Midcycle.
/An supine position.
410 Hyperfunctioning Adrenal Carcinoma, Endocr Pract. 2007;13(No. 4)
enhancement and large size, the lesion was suspicious for either a metastatic tumor or an adrenocortical carcinoma. Findings on CT scans of the thorax and magnetic reso- nance imaging of the brain were unremarkable.
The patient was referred for surgical adrenalectomy. Grossly, the tumor weighed 94 g and was 8.0 by 5.5 by 3.5 cm. Several nodules were apparent on the surface of the gland, and sectioning of the specimen showed a tumor with a soft necrotic-appearing orange core and a surround- ing rim of firm tan cortical tissue. Microscopic examina- tion revealed 11 mitotic figures per 50 high-power fields and moderate pleomorphism. There was no involvement of local lymph nodes. The tumor fulfilled the criteria for a malignant lesion on the basis of the necrosis, 11 mitoses per 50 high-power fields, and extension into periadrenal adipose tissue (15) (Table 2). The histopathologic diagno- sis was stage II adrenocortical carcinoma (Fig. 2).
After the operation, the patient was treated with taper- ing doses of hydrocortisone for 4 months. Postoperatively, all steroid hormone values (after 24 hours without hydro- cortisone therapy) returned to either normal or even subnormal values (Table 1). At 9 months postoperatively, no evidence of tumor recurrence was noted on either biochemical or radiologic testing.
DISCUSSION
In the current report, we demonstrate a rare case of adrenocortical carcinoma causing concurrent hypercorti- solism, hyperandrogenism, and mineralocorticoid excess with accompanying clinical sequelae. The presence of the various clinical manifestations of hormone excess implies that this carcinoma was a functional tumor. Further sup- port for the functional nature of the patient’s tumor is found by analyzing the ß-catenin staining pattern. Activation of the Wnt signaling pathway by means of ß- catenin has been implicated in adrenocortical tumorigene-
| Feature | Patient data |
|---|---|
| Nuclear grade III or IV | III |
| Mitotic rate >5 per 50 high-power fields | 11 |
| Atypical mitoses | Present |
| Clear cells ≤25% of tumor | Yes |
| Diffuse architecture | Present |
| Necrosis | Present |
| Invasion of | |
| Venous structures | Absent |
| Sinusoidal structures | Absent |
| Tumor capsule | Present |
| Mib (Ki67)-expressing cells | Not assessed |
| *Reported in Weiss (15), 1984. | |
sis. A defect in the ß-catenin gene inhibits ß-catenin degradation and allows the protein to activate the Wnt sig- naling pathway constitutively (16). The defect is quanti- fied by enhanced cytoplasmic or nuclear accumulation (or both) of ß-catenin (16). This phenomenon has been shown to occur frequently in both benign and malignant adreno- cortical tumors, but it rarely occurs in functional tumors (16). Immunohistochemical staining of our patient’s adrenocortical carcinoma for ß-catenin revealed only a membranous location of ß-catenin. Therefore, the staining pattern is consistent with a functional adrenocortical tumor because no staining was evident in the cytoplasm or nucleus.
Most adrenocortical tumors are monoclonal lesions (7). Adrenocortical carcinomas derived from the zona fas- ciculata often manifest with a block in 11ß-hydroxylase, the enzyme that catalyzes the conversion of 11-deoxycor- tisol to cortisol (Fig. 3) (17). This block results in an increased ratio of 11-deoxycortisol to cortisol (18). Such patients, nonetheless, present with cushingoid features, probably because the enzyme block is only partial and the tumors tend to be large and highly vascularized, delivering high amounts of cortisol to the peripheral blood (19). Although levels of 11-deoxycortisol were not measured in our patient, we can assume that there is some block in the 11ß-hydroxylase enzyme, in light of the high levels of DOC, a mineralocorticoid precursor just proximal to the 11-hydroxylase step. Thus, the zona fasciculata is the most likely zone of origin for the lesion in this patient.
The rapid onset of our patient’s signs and symptoms of Cushing’s syndrome raised clinical suspicion for the presence of hypercortisolism in conjunction with a possi-
ble malignant lesion. This suspicion was confirmed by the elevated random serum, midnight salivary, and 24-hour urine cortisol levels in the setting of suppressed corti- cotropin. The profoundly increased testosterone and androstenedione levels were unexpected at the time of her consultation because of the absence of physical manifesta- tions of hyperandrogenism. The disparity between her physical appearance and the laboratory results may be
explained by the rapid nature of her tumor growth. It may be postulated that, with time, the classic signs of viriliza- tion would have emerged. Primary hypermineralocorti- coidism seemed likely because of the findings of hypertension and refractory hypokalemia. In this situation, however, one would usually expect to find abnormally high levels of aldosterone accompanied by suppressed plasma renin activity. In our patient, the initial aldosterone
Cholesterol
Desmolase
Pregnenolone
17a Hydroxylase
170H-Pregnenolone
C17- Lyase
Dehydroepiandrosterone
3฿ Hydroxysteroid dehydrogenase (3ß HSD)
3ß HSD
3฿ HSD
Progesterone
170H-Progesterone
Androstenedione
21-Hydroxylase
21-Hydroxylase
Peripheral Tissues
Deoxycorticosterone
11-Deoxycortisol
Testosterone
11ß Hydroxylase
11ß Hydroxylase
Corticosterone
Cortisol
18-Hydroxylase
180H-Corticosterone
18-Oxidase
Aldosterone
Fig. 3. Enzymatic pathway for aldosterone and cortisol. Adapted from Deaton M, Glorioso J, McLean DB. Am Fam Physician. 1999;59:1190-1196.
412 Hyperfunctioning Adrenal Carcinoma, Endocr Pract. 2007;13(No. 4)
level was <1 ng/dL, and the plasma renin activity was only minimally suppressed. This apparent paradox was resolved by the discovery of dramatically increased levels of DOC, the biologically active precursor to aldosterone. There are very few cases in the medical literature of adrenocortical carcinoma producing elevated DOC levels (8-14).
CONCLUSION
Interestingly, although only a few cases of DOC- secreting adrenal carcinomas have been described, we postulate that concurrent secretion of DOC, cortisol, and androgens by these tumors may occur more frequently than previously recognized, in light of the ability of the zona fasciculata to produce all these steroid hormones and precursors. In the past, signs of hyperaldosteronism in ACC were attributed to the ability of excess glucocorti- coids to stimulate the mineralocorticoid receptor to pro- duce aldosterone. Nonetheless, it is possible that previously reported cases of hypertension and hypokalemia in patients with ACC-mediated Cushing’s syndrome were caused primarily by excess DOC secre- tion, rather than the aforementioned phenomenon. The advent of DOC assays will now help elucidate the relative contribution of mineralocorticoids versus glucocorticoids in ACC-associated hypertension and hypokalemia.
DISCLOSURE
The authors have no conflicts of interest to disclose.
REFERENCES
1. Cutler SJ, Young JL, eds. Third National Cancer Survey: Incidence Data. Bethesda, MD: US Department of Health, Education and Welfare, Public Health Service, National Institutes of Health, National Cancer Institute, 1975. National Cancer Institute Monograph 41.
2. Ng L, Libertino JM. Adrenocortical carcinoma: diagno- sis, evaluation and treatment. J Urol. 2003;169:5-11.
3. Crucitti F, Bellantone R, Ferrante A, Boscherini M, Crucitti P (ACC Italian Registry Study Group). The Italian registry for Adrenal Cortical Carcinoma: analysis of a multiinstitutional series of 129 patients. Surgery. 1996; 119:161-170.
4. Hogan TF, Gilchrist KW, Westring DW, Citrin DL. A clinical and pathological study of adrenocortical carcino- ma: therapeutic implications. Cancer. 1980;45:2880-2883.
5. Xiao XR, Ye LY, Shi LX, Cheng GF, Li YT, Zhou BM. Diagnosis and treatment of adrenal tumours: a review of 35 years’ experience. Br J Urol. 1998;82:199-205.
6. Flack MR, Chrousos GP. Neoplasms of the adrenal cor- tex. In: Holland JF, Frei E III, Bast RC Jr, Kufe DW Jr, Morton DL, Weichselbaum RR, eds. Cancer Medicine. 4th ed. Baltimore, MD: Williams & Wilkins, 1997: 1563-1570.
7. Latronico AC, Chrousos GP. Extensive personal experi- ence: adrenocortical tumors. J Clin Endocrinol Metab. 1997;82:1317-1324.
8. Mussig K, Wehrmann M, Horger M, Maser-Gluth C, Haring HU, Overkamp D. Adrenocortical carcinoma pro- ducing 11-deoxycorticosterone: a rare cause of mineralo- corticoid hypertension. J Endocrinol Invest. 2005;28: 61-65.
9. Kelly WF, O’Hare MJ, Loizou S, Davies D, Laing I. Hypermineralocorticism without excessive aldosterone secretion: an adrenal carcinoma producing deoxycortico- sterone. Clin Endocrinol (Oxf). 1982;17:353-361.
10. Irony I, Biglieri EG, Perloff D, Rubinoff H. Pathophysiology of deoxycorticosterone-secreting adrenal tumors. J Clin Endocrinol Metab. 1987;65:836-840.
11. Powell-Jackson JD, Calin A, Fraser R, et al. Excess deoxycorticosterone secretion from adrenocortical carcino- ma. Br Med J. 1974;2:32-33.
12. Makino K, Yasuda K, Okuyama M, Ojima M, Sasano N, Miura K. An adrenocortical tumor secreting weak min- eralocorticoids. Endocrinol Jpn. 1987;34:65-72.
13. Egoshi K, Masai M, Nagao K, Ito H. 11-Deoxycortico- sterone-producing adrenocortical carcinoma. Urol Int. 1998;61:251-253.
14. Furuse H, Watase H, Ihara H, et al. Deoxycortico- sterone-producing adrenocortical carcinoma-a case report [article in Japanese]. Nippon Hinyokika Gakkai Zasshi. 1995;86:957-960.
15. Weiss LM. Comparative histologic study of 43 metasta- sizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984;8:163-169.
16. Tissier F, Cavard C, Groussin L, et al. Mutation of beta- catenin in adrenocortical tumors: activation of the Wnt sig- naling pathway is a frequent event in both benign and malignant adrenocortical tumors. Cancer Res. 2005;65: 7622-7627.
17. Rainey WE, White PC. Functional adrenal zonation and regulation of aldosterone biosynthesis. Curr Opin Endocrinol Diab. 1998;5:175-182.
18. Lipsett MB, Hertz R, Ross GT. Clinical and pathophysi- ologic aspects of adrenocortical carcinoma. Am J Med. 1963;35:374-383.
19. Levine AC, Mitty HA, Gabrilove JL. Steroid content of the peripheral and adrenal vein in Cushing’s syndrome due to adrenocortical adenoma and carcinoma. J Urol. 1988; 140:11-15.