Adrenal Insufficiency Secondary to Carcinoma Metastatic to the Adrenal Gland
LESLIE R. SHEELER, MD, JAMES H. MYERS, MD, JOHN J. EVERSMAN, MD, AND HARRIS C. TAYLOR, MD
Four patients are reported in whom adrenocortical insufficiency developed consequent to carcinoma metastatic to the adrenal glands. Recognition and treatment of this entity may lead to palliation of symptoms and prolongation of useful life. The computerized axial tomographic scanner is a valuable diagnostic aid in diagnosing adrenal enlargement.
Cancer 52:1312-1316, 1983.
A DRENOCORTICAL insufficiency resulting from met- astatic carcinoma is a seldom recognized and re- ported condition. Thomas Addison, however, in his original report1 of the syndrome bearing his name, in- cluded a 60-year-old woman with breast cancer and bi- lateral adrenal involvement.
In this report, we describe four patients with adreno- cortical insufficiency from metastatic cancer to the adrenal glands. We also emphasize the value of computerized axial tomographic (CAT) scanning of the adrenals to assist in the diagnosis of this entity.
Case Reports
Case 1
A 52-year-old man, previously in good health, was admitted to the hospital in July 1977 for evaluation of easy fatigability and a 27 kg weight loss developing over the preceding 9 months. He also complained of frequent hiccups. He had been admitted to another hospital in June 1977 for investigation of these complaints. Negative studies included an intravenous pyelogram, upper gastrointestinal and colon x-rays, and a chest x-ray. On initial examination, he appeared ill and increased pigmentation was noted over the entire body. His blood pres-
sure was 92/68 mm Hg supine and was inaudible on assuming the erect posture. The pulse rate was 88 beats per minute. The remainder of the physical examination was unremarkable. The initial laboratory data were as follows: serum sodium, 128 mEq/L; potassium, 5.7 mEq/L; blood urea nitrogen (BUN), 40 mg/dl; alkaline phosphatase, 280 mU/L; and free thyroxine index, 0.92 (normal, 0.86-1.07). The adrenal antibody titer was negative and an intermediate strength tuberculin skin test was negative. Roentgenogram of the chest was normal.
An adrenocorticotropic hormone (ACTH) stimulation test was performed infusing 40 units of ACTH every 12 hours over a 48-hour period,2 while the patient took dexamethasone, 0.5 mg orally every 6 hours. Table 1 demonstrates the results of the stimulation test which are consistent with primary adre- nocortical insufficiency. The patient was placed on cortisone acetate, 25 mg twice daily and initially felt much improved. However, he returned in September 1977 complaining of dys- pnea on exertion during the preceding 11 days. He was found to have a 100% pneumothorax on the right side requiring a chest tube. Upon re-expansion of the right lung, four nodular densities were observed in the right lung field. The patient underwent an open lung biopsy and multiple pulmonary nod- ules were observed. The biopsy showed large cell undifferen- tiated carcinoma.
The patient was discharged on October 10, 1977, but re- turned on December 21, 1977 again complaining of shortness of breath. The chest film again revealed a 100% pneumothorax, this time on the left, requiring a chest tube. Hospitalization was complicated by aspiration pneumonia, hypotension, and oliguric renal failure. The patient died on January 5, 1978.
A postmortem examination revealed primary adrenocorti- cal carcinoma of the left adrenal with metastatic tumor to both lungs, both kidneys, right adrenal gland, gallbladder, stomach, small bowel, liver, mesenteric, aortic and retroperitoneal lymph nodes, thyroid and brain. Both adrenals were enlarged, the right weighing 20 g and the left 90 g. Each was completely
From the Department of Endocrinology and Metabolism, The Cleve- land Clinic Foundation and the Cleveland Clinic Educational Foun- dation, and the Division of Endocrinology and Metabolism at the Luth- eran Medical Center Cleveland, Ohio.
Address for reprints: Harris C. Taylor, MD, Division of Endocrinology and Metabolism, Lutheran Medical Center, 2609 Franklin Boulevard, Cleveland, OH 44113.
The authors thank Ms. Laurie Urankar, Ms. Maxine Shankman and Ms. Colleen Grubbs for fine secretarial assistance. Prasadarao G. Kon- dapalli kindly referred Patient 3.
Accepted for publication July 2, 1982.
| Normals* | Urine 17- hydroxycorticoids 1- 9 mg/24 hr | Urine 17- ketosteroids 6-21 mg/24 hr | Urine creatinine mg/24 hr | Urine free cortisol 80-370 µg/24 hr | Serum cortisol ug/dl | Serum aldosterone; ng/dl |
|---|---|---|---|---|---|---|
| Patient 1 | ||||||
| Day 1 | 2.3 | 8.0 | 1040 | 100.0 | 3.1 (After 24 hr) | |
| Day 2 | 2.0 | 7.0 | 984 | 42.6 | 9.0 (After 48 hr) | |
| Patient 2 | ||||||
| Day 1 | 2.6 | 6.0 | 893 | 41.6 | 2.7 (After 24 hr) | |
| Day 2 | 4.0 | 8.4 | 1050 | - | 7.6 (After 48 hr) | |
| Patient 3 | ||||||
| Day 1 | 13.0 | 8.2 | 1100 | - | 18.5 (before ACTH infusion) | 1.6 (before ACTH infusion) |
| 16.2 (After 24 hr) | 2.9 (After 3 hr) | |||||
| Day 2 | 10.9 | 11.0 | 1100 | - | 14.5 (After 48 hr) | 2.0 (After 8 hr) |
* Normal values are for unstimulated state. During 48-hour ACTH infusion, normal values should be 65 ± 10 ug/dl at 24 hours for plasma cortisol and >47 mg/24 hours (72 ± 7.2) for 17-hydroxycorticoids by
the end of the test.2
t Normal fasting recumbent aldosterone on normal Na’ intake 3- 16 ng/dl.
replaced by tumor with no normal adrenal tissue remaining. A mucin stain was negative.
Case 2
A 75-year-old white woman was first seen in July 1979 at the Cleveland Clinic complaining of fatigue and a 13 kg weight loss over the preceding 6 months. Her past history was significant in that the patient had a right radical mastectomy 10 years previously for breast cancer. On physical examination, her blood pressure was 92/58 mm Hg supine and 90/60 mm Hg standing, and she weighed 55 kg. Generalized increased pigmentation of the skin was noted being most prominent over the elbows and around the mouth. There were many dark freckles over the face and extremities. Axillary and pubic hair were sparse. Laboratory data revealed a hemoglobin of 13.8 g, serum potassium of 5.4 mEq/L, serum sodium of 127 mEq/L and a BUN of 27 mg/ dl. A Cortrosyn (Organon Inc., West Orange, NJ) stimulation test was done injecting 0.25 mg of Cortrosyn intramuscularly (IM). The preinjection plasma cortisol was 6.6 ug/dl and the 30 minute post injection level was 8.4 ug/dl. An adrenal antibody titer was negative. Basal afternoon ACTH level was 365 pg/ml (normal, 6-56) with a simultaneous plasma cortisol of 4.7 ug/ dl. The results of a continuous, 48-hour ACTH intravenous infusion are shown in Table 1. During the infusion, the patient received 0.5 mg of dexamethasone every 12 hours and felt better with the first dose. Because of the absence of a response to ACTH and the history of breast cancer, a CAT scan of the adrenals was obtained and showed both adrenals to be signif- icantly enlarged (Figs. 1 and 2). A fine-needle adrenal aspiration was attempted under the guidance of the computerized to- mographic scanner, but an adequate specimen was not obtained. The patient was discharged on cortisone acetate and Florinef (Squibb & Sons, ER, Princeton, NJ), and felt entirely well for approximately 1 year. In August 1980, she returned complaining
of abdominal pain. Laparotomy revealed widespread metastatic breast cancer with replacement of both adrenals by tumor. The patient was placed on hormone therapy for breast cancer and was last seen in August 1981. She has no abdominal pain, but has ascites and edema of her legs.
Case 3
A 65-year-old white man with an 80-pack per year history of cigarette smoking, presented with a 29.5 kg weight loss of 5 months’ duration. Additional complaints included increasing dyspnea and chest pain. Chest x-ray revealed a cavitating lesion in the apical posterior segment of the left upper lobe. On bron- choscopy this proved to be a squamous cell carcinoma. On admission to the hospital, serum sodium was 134 mEq/L, po-
INF. VENA CAVA
R. ADRENAL
L. ADRENAL
tassium 4.8 mEq/L, and BUN 31 mg/dl. On the ninth hospital day, the patient’s temperature suddenly rose to 40.2℃ rectally while the blood pressure, previously in the range of 120/70 mm Hg dropped to 48 mm Hg by palpation and the pulse increased to 118 beats per minute. The serum sodium declined to 124 mEq/L and the potassium increased to 6.0 mEq/L. The primary physician undertook therapy with a dopamine infusion and hydrocortisone hemisuccinate 500 mg intravenously (IV) every 12 hours as well as intravenous fluids after obtaining multiple blood and urine cultures. No antibiotics were given and no serum cortisol was drawn. The patient’s clinical condition rapidly improved. The fever disappeared and the hydrocortisone and dopamine were discontinued. All cultures were negative. A repeat episode occurred on the 15th hospital day, characterized by an increase of temperature to 40.3℃ rectally, a drop of blood pressure to 60 mm Hg by palpation, with an increase of the pulse to 130 beats per minute. Serum sodium was 133 mEq/
A
A
K
K
R
L.
L, potassium 5.2 mEq/L, and BUN 33 mg/dl. Multiple cultures were again negative and similar therapy was again instituted with complete resolution of the fever, hypotension and tachy- cardia. Intravenous hydrocortisone was then changed to IM cortisone acetate 50 mg every 12 hours. On this regimen, the serum sodium increased to 140 mEq/L, the serum potassium decreased to 3.4 mEq/L, and the BUN decreased to 18 mg/dl on the 23rd hospital day. The patient was then seen in con- sultation by one of the authors. He was noted to have diffuse increased pigmentation over the entire body, more in the exposed areas, during the middle of November. A 48-hour ACTH in- fusion was begun 36 hours after the last IM cortisone acetate was given and the patient placed on dexamethasone 0.5 mg orally every 6 hours. Results are shown in Table 1. At the conclusion of this diagnostic measure, maintenance therapy was instituted with cortisone acetate 25 mg orally every 8 hours and liberal salt intake. A CAT scan of the adrenal glands revealed the left and right suprarenal areas to be replaced by 7 to 8-cm masses (Fig. 3). Subsequent to discharge, the patient returned with postural hypotension. The recumbent blood pressure of 120/70 mm Hg decreased to less than 80 mm Hg on standing and the patient was unable to remain upright. Treatment for acute adrenal insufficiency was undertaken with a continuous infusion of 3000 ml of normal saline and 300 mg hydrocortisone hemisuccinate over 24 hours. The blood pressure was normalized and the postural hypotension disappeared. A serum cortisol drawn during the postural hypotension at 3:30 PM was 7.2 ug/ dl while the plasma ACTH level simultaneously was 221 pg/ ml (normal, <20-50 pg/ml).
Case 4
A 70-year-old white man was being evaluated for radiotherapy of a large cell primary lung cancer. He complained of weight loss and diminished appetite for the preceding three months. On examination, the patient weighed 43 kg and appeared le- thargic and cachectic. Blood pressure was 103/80 mm Hg. There was no significant hyperpigmentation. The initial laboratory data revealed a serum sodium of 112 mEq/L, potassium of 5.2 mEq/L and BUN of 7 mg/dl. A Cortrosyn stimulation test was done and revealed a baseline cortisol of 10.6 ug/dl, and a 1- hour postinjection cortisol level of 14.6 ug/dl. A 48-hour2 con- tinuous ACTH infusion was then performed and the results are shown in Table 2. Dexamethasone was given during the infusion resulting in marked increase in alertness. Three days after the infusion a fever of 39℃ developed and the systolic blood pressure diminished to 80 mm Hg. Treatment for acute adrenal insuf- ficiency was begun with intravenous and intramuscular hydro- cortisone and normal saline. The patient’s condition stabilized within 12 hours and he became afebrile. A computerized axial tomographic scan of the abdomen was performed and revealed bilateral suprarenal masses in the area of the adrenal glands (Fig. 4). The right mass measured approximately 9 cm in di- ameter and the left mass approximately 3.5 cm in diameter. He was discharged on cortisone acetate, the serum sodium having increased to 128 mEq/L. His clinical condition was improved.
Results
Failure of urine 17-hydroxycorticoids and serum cor- tisol to demonstrate a significant increase in response to ACTH infusion2 in Patients 1, 2, and 3, and failure of serum cortisol and aldosterone to increase normally in Patient 4, confirms the clinical diagnosis of adrenal in- sufficiency biochemically. That the adrenal insufficiency was primary rather than secondary is verified biochem- ically by the elevated afternoon ACTH determination in Patients 2 and 3 and anatomically by examination of the adrenal glands in Patients 1 and 2. Only in Patient 4 is there lack of additional morphologic or biochemical con- firmation. However, radiographic evidence of complete replacement of both adrenals by large masses suggest that the patient’s adrenal insufficiency is primary. The some- what higher than anticipated first day values for urinary 17-hydroxycorticoids and serum cortisol with subsequent decrease in Patient 3 likely reflects the depot effect of the previously administered intramuscular cortisone acetate.
Discussion
Metastases to the adrenal glands from carcinoma is quite common. An analysis of 354 autopsy cases3 of met- astatic carcinoma to the adrenals showed that 41% had bilateral adrenal involvement. Willis,4 in a series of 500 autopsy cases of patients with cancer, found adrenal me- tastases in 9%. Glomsett5 analyzed 445 autopsy cases of metastatic carcinoma and found the adrenals to be in- volved in 25% of the cases, carcinoma of the lung and breast proving to be the most common source of such tumors. Bullock and Hirst6 found evidence of adrenal metastases in 28.7% of bronchogenic carcinomas and 12.8% of breast cancers examined. Sahagian-Edwards and Holland3 found a 42% incidence of adrenal involvement with lung cancer and 34% incidence with breast cancer. Clinical adrenocortical insufficiency, however, from met- astatic carcinoma is uncommon. This could be explained by the fact that 90% of the adrenal cortex must be de- stroyed before hypofunction occurs.7
In 1965, Hill and Wheeler8 reviewed the literature concerning adrenal insufficiency secondary to metastatic carcinoma, noting only 22 reported cases. In only 5 of these were steroid measurements available. Carcinoma of the lung was the most common primary tumor oc- curring in 15 of 22 cases. In contrast, 7 years later, Vie- wig et al.9 found only seven cases of tumor caused ad- renocortical insufficiency that were well documented and contained steroid measurements through 1972. There is one well documented case of breast cancer cited
| Hours | |||||
|---|---|---|---|---|---|
| 0 | 3 | 8 | 24 | 48 | |
| S. Cortisol (µg/dl) | 5.7 | 20.6 | 19.5 | 17.2 | 18.6 |
| S. Aldosterone (ng/dl) | 2.4 | 2.2 | |||
Normal fasting recumbent aldosterone on normal Na’ intake 3-16 ng/dl.
in their report.11 Another case reported in 1960 is very likely to represent adrenal failure secondary to meta- static breast cancer, but steroid measurements were lack- ing.10 To the best of our knowledge, there has been only one previously reported case of adrenal insufficiency from metastatic primary adrenocortical carcinoma.12
It is surprising that adrenocortical insufficiency from metastatic carcinoma is so rarely reported when one considers the frequency of metastatic carcinoma to the adrenals. This may be due to the fact that the symptoms of adrenal insufficiency are attributed to the dissemi- nated cancer. Recognition and treatment of adrenocor- tical insufficiency in patients with carcinoma can lead to palliation of symptoms and prolongation of useful life. This is best exemplified by our Patient 2, where the symptoms of adrenal insufficiency antedated any other signs of disseminated cancer. She has lived an additional 2 years after adrenal failure was diagnosed. The symp- toms in the first patient appear to be largely due to his Addison’s disease. An extensive investigation for malig- nancy was negative. A CAT scan would have very likely revealed adrenal pathologic features. His metastatic dis-
RIGHT ADRENAL
LEFT ADRENAL
ease caused death within 6 months, despite a brief dra- matic improvement in his clinical status. We strongly emphasize the value of CAT scanning of the adrenal in arriving at the diagnosis of metastatic disease in Patients 2, 3 and 4. We recommend the use of CAT scanning in all cases of primary adrenal failure where the cause is uncertain. With continuing improvement in cancer therapy, recognition and treatment of this entity will assume increased importance.
REFERENCES
1. Addison T. On the constitutional and local effects of disease of suprarenal capsules. London: S. Highley, 1865. Reprinted in Medical Classics 1937; 2:244-280.
2. Rose LI, Williams GH, Jagger PI, Lauler DP. The 48-hour ad- renocorticotrophin infusion test for adrenocortical insufficiency. Ann Intern Med 1970; 73:49-54.
3. Sahagian-Edwards A, Holland JF. Metastatic carcinoma to the adrenal glands with cortical hypofunction. Cancer 1954; 7:1242-1245.
4. Willis RA. The spread of tumors in the human body, ed. 2. St. Louis: CV Mosby, 1952.
5. Glomsett DA. The incidence of metastasis of malignant tumors of the adrenal. Am J Cancer 1938; 32:57.
6. Bullock WK, Hirst AE. Metastatic carcinoma of the adrenal. Am J Med Sci 1953;226:521.
7. Rosenthal FD, Davies MA, Burden AC. Malignant disease pre- senting as Addison’s disease. Br Med J 1978; 1:1591-1592.
8. Hill GJ II, Wheeler HB. Adrenal insufficiency due to metastatic carcinoma of the lung: Case report and review of Addison’s disease caused by adrenal metastases. Cancer 1965;18:1467-1473.
9. Vieweg WVR, Reitz RE, Weinstein RL. Addison’s disease sec- ondary to metastatic carcinoma: An example of adrenocortical and adrenomedullary insufficiency. Cancer 1973; 31:1240-1243.
10. Galloway JA, Perloff WH. Addison’s disease secondary to ad- renocortical destruction by metastatic cancer of the breast. Am J Med 1960; 28:156.
11. Alpers DH, Engelman K, Foley FD. Addison’s disease second- ary to carcinoma of the breast. Ann Intern Med 1962; 57:464-467.
12. Heath H III, Bergevin RD. Adrenal insufficiency resulting from metastasis of nonfunctioning adrenocortical carcinoma. Medical Annals of District of Columbia 1973; 42:545-547.