ADDISON’S DISEASE SECONDARY TO METASTATIC CARCINOMA: AN EXAMPLE OF ADRENOCORTICAL AND ADRENOMEDULLARY INSUFFICIENCY
W. V. R. VIEWEG, CDR., MC, USN,* RICHARD E. REITZ, MD, AND RICHARD L. WEINSTEIN, MD
Adrenal insufficiency developed in a 42-year-old woman with carcinoma of the lung. Adrenocortical production was assessed by the excretory rates of mineral- ocorticoids (aldosterone, deoxycorticosterone, corticosterone), glucocorticoids (17-hydroxysteroids), and 17-ketosteroids, while adrenomedullary production was assessed by the excretory rate of epinephrine. Additionally, plasma cortisol was measured before and after adrenocorticotrophin (ACTH) stimulation, and urinary epinephrine was determined before and after insulin-induced hypo- glycemia. These studies revealed a reduction in adrenocortical and adrenomed- ullary excretion as well as an absence of adrenocortical and adrenomedullary reserve. Seven other cases of adrenal insufficiency secondary to metastatic carcinoma were found in the literature in which steroid studies documented the diagnosis. These cases are reviewed and compared to the present case. Although carcinoma frequently metastasizes to the adrenal, development of adrenal insufficiency is rare and recognition occurs even less frequently.
A DRENAL INSUFFICIENCY SECONDARY TO META- static carcinoma accounts for less than 1% of the reported cases of Addison’s disease.9 We describe here a case in which adrenocorti- cal and adrenomedullary functions were simul- taneously assessed. Additional cases in which steroid studies were performed are reviewed and compared to the present case.
MATERIALS AND METHODS
Urinary excretion of 17-hydroxysteroids was measured by the Peterson modification of the Porter-Silber method.14 Urinary excretion of deoxycorticosterone and corticosterone was measured by the technique of Weinstein et al.18,19 and aldosterone by the method of Kli-
From the Medical Service and the Clinical Investiga- tion Center, Naval Hospital, Oakland, Calif., and the Department of Medicine, University of California, San Francisco, Calif.
* Presently assigned to the Cardiology Service, Naval Hospital, San Diego, Calif.
Address for reprints: R. L. Weinstein, MD, Clinical Investigation Center, Naval Hospital, Oakland, Calif. 94627.
The opinions or assertions contained herein are those of the authors and are not to be construed as official or as necessarily reflecting the views of the Medical De- partment of the Navy or the Naval Service at large.
Received for publication November 27, 1972.
man and Peterson.13 Urinary excretion of epi- nephrine was determined by the method of Crout.6 Plasma cortisol was measured by the double-isotope dilution derivative method.12
CLINICAL SUMMARY
A 42-year-old Caucasian woman presented to the Oakland Naval Hospital in May 1968, with acute cardiac tamponade. She weighed 135 lb. The blood pressure was 115/90 mg. Complete blood count and serum electrolytes were normal. A pericardiocentesis revealed bloody fluid with malignant cells. A biopsy specimen of the pericardium demonstrated poorly differentiated adenocarcinoma. Neither radiotherapy nor chemotherapy was adminis- tered.
In December 1968, the patient’s weight was 125 lb., and blood pressure was 112/90 mg. Laboratory and radiographic studies were nor- mal. A right hilar mass was noted on the chest x-ray in October 1969, and cytologic examina- tion of the sputum revealed malignant cells. A course of radiotherapy was directed to the right hilar area, and this was followed by chemotherapy with Cytoxan (cyclophos- phamide, Mead Johnson) and vincristine.
| Mineralocorticoids* | Glucocorticoidst | 17-Ketosteroids* | |||
|---|---|---|---|---|---|
| pg/24 hrs. | mg/24 hrs. 17-OHS | mg/24 hrs. 17-KS | |||
| DOC | B | ALDO | |||
| R. B. (Addisonian) | 0.9 | 5.1 | 0.8 | 0.8 | 2.1 |
| Normal range | 4-16 | 90-315 | 5-20 | 3-9 | 6-15 |
* Deoxycorticosterone (DOC); corticosterone (B); aldosterone (ALDO).
+ 17-hydroxysteroids (17-OHS).
* 17-ketosteroids (17-KS).
The patient was subsequently admitted in January 1970, with a 3-month history of pro- gressive anorexia, weight loss, weakness, dizzi- ness, abdominal pain, and darkening of the skin. The supine blood pressure was 90/60 mg which decreased to 70/40 mg in the seated posture. The skin was dry, and dark pigmen- tation was noted over the elbows, knees, meta- carpals, bucccal mucosa, tongue, and lower lip. Axillary and pubic hair were decreased, and there was wasting and weakness of all extremi- ties. Pertinent laboratory studies included: he- matocrit 32%; WBC 3,700 with 7% eosino- phils; serum sodium 129 mEq/liter; serum chloride 89 mEq/liter; serum potassium 5.0 mEq/liter; serum bicarbonate 20.0 mEq/liter, and blood urea nitrogen 29 mg/100 ml.
A diagnosis of adrenal insufficiency was es- tablished. The patient was treated with corti- sone acetate (25 mg in the morning and 12.5 mg in the evening) and 9a-fluorohydro- cortisone (0.05 mg daily). There was pro- gressive decrease in skin pigmentation, and the blood pressure and serum electrolytes returned to normal.
The patient was readmitted in March 1970, with epigastric pain radiating posteriorly. An intravenous pyelogram revealed no visualiza- tion of the upper pole of the left kidney. The patient died shortly thereafter. Autopsy exam- ination revealed a primary epidermoid carci- noma in the right lung. A 7 x 6 x 5 cm spher- ical mass had replaced the upper pole of the
left kidney. The right kidney appeared nor- mal; above the right kidney a mass occupied the appropriate location for the adrenal gland. Microscopic examination revealed that both adrenal glands were replaced with nests and sheets of malignant epithelial cells with individual cell keratinization and pearl forma- tion identical to the primary tumor. No evi- dence of normal adrenal tissue was demon- strated.
RESULTS
Tests of Adrenal Function
Adrenocortical: Urinary excretion of deoxy- corticosterone (DOC) 0.9 ug/24 hrs., corticos- terone (B) 5.1 ug/24 hrs., aldosterone (ALDO) 0.8 µg/24 hrs., 17-hydroxysteroids (17-OHS) 0.8 mg/24 hrs., and 17-ketosteroids (17-KS) 2.1 mg/24 hrs. were markedly below normal (Table 1).
ACTH, 40 units in 500 ml of 0.9% sodium chloride, was administered intravenously over 8 hours daily for 3 days. Plasma cortisol (F) and urinary 17-hydroxysteroids were deter- mined before and during ACTH infusion. Basal values for plasma cortisol, 2.7-3.0 ug/100 ml, and urinary 17-hydroxysteroids, 0.9-1.1 mg/24 hrs., were low and no rise was observed during ACTH administration (Table 2).
Adrenomedullary: A 6-hour collection for urinary epinephrine was performed before
| No. of days of treatment with ACTH | Plasma cortisol ug/100 ml | Urinary 17-hydroxysteroids mg/24 hrs. | ||
|---|---|---|---|---|
| 8 a.m. | 12 p.m. | |||
| R. B. | Day 1 | 2.7 | 3.2 | 1.2 |
| (Addisonian) | Day 2 | 2.8 | 2.9 | 0.9 |
| Day 3 | 3.0 | 3.1 | 1.0 | |
| Normal range | 5-25 | 30-55 | 8-35 | |
* ACTH, 40 U intravenously over 8 hours daily for 3 days.
and after a standard insulin tolerance test. Both the basal and post-insulin excretory rates of epinephrine (0.9 ug/6 hrs. and 1.1 ug/6 hrs.) were similar to levels found in patients with tuberculous Addison’s disease (1.0 ± 0.7 SEM µg/6 hrs.) during insulin-induced hy- poglycemia.17
DISCUSSION
In the present case, adrenocortical failure secondary to metastatic carcinoma resulted in a diminution of mineralocorticoid, glucocorti- coid, and 17-ketosteroid hormones. The de- creased excretion of aldosterone, and to a lesser extent deoxycorticosterone and corticos- terone, was reflected by the development of hyponatremia, hyperkalemia, dehydration, and azotemia. Decreased concentrations of uri- nary 17-hydroxysteroids and 17-ketosteroids, and the inability to increase plasma cortisol during 3 days of ACTH stimulation, indi- cated a lack of adrenocortical reserve. In- creased pigmentation indicated elevated levels of ACTH and ß-melanocyte-stimulating hor- mone (B-MSH),1 an expected response to pri- mary adrenocortical failure.
Seven additional case reports of adrenal in- sufficiency secondary to metastatic carcinoma confirmed by steroid measurements have been described.2,4,10,15 Urinary excretion of 17-hy- droxysteroids and/or 17-ketosteroids was de- creased in each case. ACTH stimulation tests performed in four subjects also revealed an absence of adrenocortical reserve.
A lack of adrenomedullary reserve has been described in tuberculous adrenal in- sufficiency.17 Necropsy studies in such cases have revealed that the medulla is first com- pletely destroyed and then the process slowly involves the cortex.3 In most cases of idi- opathic Addison’s disease, the adrenal me- dulla is normal or only slightly atrophied.8
The frequency of metastases to the adrenal glands from all types of neoplasms is approxi-
mately 10%.20 However, in a series of 566 cases of Addison’s disease, only 1% was found to be secondary to metastatic neoplasm.9 This is explained by the fact that 90% of the adre- nal cortex must be replaced by neoplasm be- fore adrenocortical insufficiency develops.5
In these patients with malignancy, the diag- nosis of adrenal insufficiency may be over- looked because the symptoms and signs of Ad- dison’s disease may be attributed to the pri- mary disease.11 The patient described herein manifested symptoms and signs of adrenal in- sufficiency approximately 3 months before the diagnosis was established. Complaints of weak- ness, weight loss, anorexia, nausea, and ab- dominal pain were attributed to carcinomato- sis. The similar features of carcinomatosis and Addison’s disease are well recognized.2,15 In this instance, the presence of pigmentation, postural hypotension and laboratory evidence of hyponatremia, hyperkalemia, and eosino- philia alerted the physician to consider adreno- cortical insufficiency.
Carcinoma of the lung was the primary tumor in this case as well as in 5 of the 7 cases reviewed while carcinoma of the breast and testis were the primary tumors in the remain- ing two cases (Table 3). Whereas the sex inci- dence in idiopathic Addison’s disease is equal,7 in the eight cases reviewed in this re- port of adrenal insufficiency secondary to met- astatic carcinoma, there were six men and two women. This distribution was not unexpected since primary carcinoma ofthe lung occurs with much greater frequency in men16 and is the most common primary tumor in patients with adrenal insufficiency secondary to meta- static carcinoma.11
Although the rarity of adrenal insufficiency in such subjects is explained by the need for almost total destruction of adrenal tissue be- fore insufficiency develops, it is likely that many cases remain undiagnosed because the symptoms and signs of Addison’s disease are attributed to the underlying malignancy.
| Butterly9 | Butterly9 | Butterly9 | Sahagian- Edwards10 | Sahagian- Edwards10 | Alpers11 | Heuson12 | Present case | |
|---|---|---|---|---|---|---|---|---|
| Age (yrs.) | 58 | 73 | 47 | 61 | 49 | 80 | 45 | 42 |
| Sex | Male | Male | Male | Male | Male | Female | Male | Female |
| Primary site | Lung | Lung | Lung | Lung | Lung | Breast | Testis | Lung |
* Steroid studies were performed in these cases which documented adrenal insufficiency.
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