Profile and Possible Origin of an Adrenocortical Carcinoma
ROBERT G. DLUHY, JOSEPH J. BARLOW, EDWARD M. MAHONEY, ROBERT L. SHIRLEY, AND GORDON H. WILLIAMS
Endocrine-Metabolic Unit and Department of Medicine, Peter Bent Brigham Hospital and Harvard Medical School, Boston, Massachusetts 02115
ABSTRACT. A 30-yr-old female with hirsutism, amenorrhea and 17-ketosteroid elevation of un- known etiology of 9-yr duration ultimately de- veloped an adrenocortical carcinoma. The patient died 4 months after removal of the primary neo- plasm of metastatic carcinoma. Studies over the 9-yr period prior to the obvious emergence of the carcinoma revealed ketosteroid suppression fol- lowing glucocorticoid administration. At autopsy,
the nontumorous adrenal gland was hyperplastic (20 g), suggesting that it might be functionally abnormal. These findings are consistent with an unusual adrenocortical carcinoma that was not autonomous; alternatively, a carcinoma could have evolved over time on a substrate of abnor- mal hyperplastic adrenal tissue. (J Clin Endocr 33: 312, 1971)
C ARCINOMA of the adrenal gland pre- sumably arises de novo in a previously normal adrenal gland, is functionally auton- omous, and often runs an inexorable and rapid course. We have recently treated a patient whose clinical course challenges many of these concepts and raises an im- portant question as to the possible origins and autonomous nature of this neoplasm.
Materials and Methods
Twenty-four hr urines were collected from 7 AM to 7 AM and kept refrigerated or frozen for measurement of 17-hydroxy corticosteroids and 17-ketosteroids. Adequacy of urine collections was determined by daily creatinine determina- tions. Urinary 17-hydroxy corticosteroids were measured as Porter-Silber chromogens by the method of Reddy (1) and urinary 17-ketoste- roids were measured by the Zimmermann re- action described by Peterson and Pierce (2). Tetrahydro compound S was measured by the method of Heinke, Doe and Jacobson (3).1 Pregnanetriol was measured by the method of Fotherby and Love (4) using a single isotope with chromatography.’ Urinary total estrogens were measured by a modification of the method of Hobkirk and Metcalfe-Gibson (5). Urinary free cortisol and urinary testosterone excretion
Received February 5, 1971.
Requests for reprints should be addressed to Robert G. Dluhy, M.D., Peter Bent Brigham Hos- pital, 721 Huntington Ave., Boston, Mass. 02115.
1 Performed by New England Nuclear Corpora- tion, Worcester, Mass,
were measured by the double isotope derivative method of Kliman and Peterson (6).1
Case Report
Ten yr prior to admission, age 30, this grav- ida 4, Para 3, ab. 1 patient became amenorrheic following a miscarriage. Nine yr prior to ad- mission, a laparatomy was performed for amenorrhea; a left ovarian cyst was discovered. The operative note reported that both adrenal glands were palpated and said to be normal. Treatment was bilateral ovarian wedge resec- tion but menses did not resume. Histological report described multiple hyalinized corpora albicantia and atretic follicles. Urinary 17- ketosteroids were 30 mg/day.
Eight yr prior to admission, the patient was referred to another hospital. Physical examina- tion revealed mild hirsutism on the face and ex- tremities and a male escutcheon. No other signs of virilization or features of Cushing’s syndrome were reported. Blood pressure was 120/70. The 17-ketosteroid excretion was 20.2 mg/24 hr and 17-hydroxycorticoid excretion was 4.7 mg/24 hr. Total urinary gonadotrophins were less than 6 mouse units,‘day. An endometrial biopsy re- vealed an atrophic proliferative pattern. An intravenous pyelogram was normal. A trial of glucocorticoid-induced adrenal suppression was attempted but menses did not resume.
Six yr prior to admission, the patient was placed on prednisone (5 mg by mouth 3 times daily), also without resumption of menses. The 17-ketosteroid excretion was not recorded at that time. Five yr prior to admission, after dis- continuing prednisone for several months, 17- ketosteroid excretion was 33 mg/24 hr (Table
| Medication | Creatinine (mg/24 hr) | 17-KS (mg/24 hr) | 17-OH (mg/24 hr) | |
|---|---|---|---|---|
| 9 yr PTA | None | - | 30.0 | - |
| 8 yr PTA | None | - | 20.0 | 4.7 |
| 7 yr PTA | None | - | 18.9 | - |
| 5 yr PTA | None | 1300 | 32.8 | - |
| None | 1100 | 33.6 | - | |
| 42 yr PTA | None | 1200 | 16.2 | 0 |
| Dexamethasone (2 mg/day ×3 days) | 1400 | 7.7 | 0 | |
| ACTH-2nd day (40 U iv over 8 hr | ||||
| per day) | 1300 | 27.4 | 20.6 | |
| Day after ACTH | 1100 | 18.0 | 1.3 | |
| 4 yr PTA | None | 1600 | 39.2 | 10.0 |
| None | 1200 | 37.0 | 11.0 | |
| 3 yr PTA | Prednisone (5 mg p.o., t.i.d. X4 months) | 1300 | 7.4 | . . 8.2 |
| 2 months PTA | ||||
| (surgical admission) | None | -- | 29 | --- |
| None | ----- | 45 | ---- | |
| 1 month PTA | None | -- | 170 | 9.0 |
| 2 weeks PTA | None | - | 256 | 12.1 |
| None | - | 303 | 14.3 |
1). Four and 3/4 yr prior to admission, the pa- tient was admitted for re-evaluation. Physical examination again revealed mild hirsutism without virilization. Blood pressure was 130/80. Control 17-ketosteroid excretion was 16 mg/24 hr (Table 1). There was normal 17-hydroxycor- ticoid response to low-dose dexamethasone sup- pression (0.5 mg dexamethasone every 6 hr for 3 days) and a normal response to ACTH stimu- lation (40 U over 8 hr/day for 2 days). 17- Ketosteroid excretion also declined following dexamethasone suppression and increased fol- lowing ACTH stimulation. A retroperitoneal air insufflation study was said to show a possible enlargement of the left adrenal gland but fur- ther review of these films revealed the roent- genogram was probably normal (Fig. 1). Diag- nosis at that time was acquired virilizing adre- nal hyperplasia. She was discharged on adrenal suppression with prednisone but menses did not resume. Clomiphene citrate was also tried with- out resumption of menses. On 2 occasions with- drawal bleeding did occur in response to pro- gesterone therapy.
Four yr prior to admission, off all medica- tions, 17-ketosteroid excretion was 39 mg/24 hr. Three yr prior to admission, the patient was again begun on prednisone suppression, 5 mg by mouth 3 times daily for 4 months. While on prednisone therapy, 17-ketosteroid excretion was 7.4 mg and 17-hydroxycorticoid excretion was 8.2 mg/24 hr but she remained amenor- rheic.
The patient was not seen again until 4 months prior to admission, when she noted a painless mass in her left flank. Preoperative radiographic studies with selective catheterization of the left renal artery revealed a tumor mass that was in part supplied by the renal vasculature. It was concluded that the tumor was probably a renal neoplasm possibly arising in the left lower pole of the kidney. Operation, using a thoraco-ab- dominal approach, allowed complete removal of a massive, encapsulated adrenal neoplasm which surrounded but did not invade the kid- ney. This was histologically identified as adre- nal carcinoma with microscopic capsular and lymphatic invasion but without lymph node involvement. 17-Ketosteroid excretion was 29 and 45 mg/24 hr. A postoperative liver scan revealed probable hepatic metastases and a chest roentgenogram revealed possible meta- static disease. One month prior to admission, the 17-ketosteroid excretion had increased to 175 mg/24 hr and the 17-hydroxycorticoids were 9.0 mg/24 hr. The liver was now greatly en- larged. Two weeks prior to admission, the 17- ketosteroid excretion values were 250 and 300 mg/24 hr and the patient was becoming markedly anorectic and cachectic. She was be- gun on 2 mg of dexamethasone/day and re- ferred to the Peter Bent Brigham Hospital for evaluation. Physical examination revealed a thin, cachectic-appearing female. Blood pres- sure was 120/80, pulse was 120 and regular. There was mild hirsutism on the face and ex-
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22
tremities with a male escutcheon. The liver was hard, slightly nodular and markedly enlarged, measuring 19 cm in the midclavicular line. The clitoris was not enlarged and the rectal exami- nation was unremarkable. Hemoglobin, hemato- crit, white blood cell count, blood urea nitro- gen, sodium, potassium, 2-hr post-prandial blood sugar and serum thyroxin were all within normal limits. Serum lactic dehydrogenase was markedly elevated but the bilirubin and alka- line phosphatase were normal. Liver scan re- vealed multiple defects compatible with meta- static carcinoma. The chest roentgenogram showed multiple lesions in both lung fields con- sistent with pulmonary metastases. Skeletal survey was negative for osteolytic or osteoblas- tic lesions. 17-Ketosteroid excretion was mark- edly elevated in the range of 200-300 mg/24 hr (Table 2), with normal 17-hydroxycorticoid ex- cretion values. Urinary estrogen, testosterone and tetrahydro-S excretion values were all ele-
vated above the upper limits of normal. Most striking, however, was an elevated pregnanet- riol excretion, which was in the range of 60 mg/24 hr (normal 0.1-4.0 mg/24 hr). The pa- tient was begun on ortho-para’DDD (2 g/day) and continued on dexamethasone (1 mg/day). She was unable to tolerate her medications be- cause of persistent nausea and she developed increasing abdominal pain due to rapid enlarge- ment of the liver. She was admitted for the second time to the Peter Bent Brigham Hospi- tal with jaundice, dehydration and severe cachexia; she died one week later of hepatic failure. Post-mortem examination revealed massive replacement of the hepatic parenchyma with metastatic carcinoma and there was metastatic carcinoma in both lung fields. The left retroperitoneum, site of the primary tumor, was free of neoplasm. An unexpected finding at autopsy was a markedly enlarged remaining right adrenal gland which weighed 20 g. Histo-
PROFILE OF AN ADRENAL CARCINOMA
| Creatinine (mg/ 24 hr) | 17-KS (mg/ 24 hr) | 17-OH (mg/ 24 hr) | Estrogen (ug / 24 hr) | Testos- terone (ug / 24 hr) | Free Cortisol (ug / 24 hr) | THS (mg/ 24 hr) | Preg nane- triol (mg/ 24 hr) | |
|---|---|---|---|---|---|---|---|---|
| Normal values | - | 5-15 | 0-10 | 15-65 | 0-20 | 20-90 | 0.1-1.0 | 0.1 -- 4.0 |
| 1176 | 213 | 2.5 | - | - | - | - | - | |
| 1440 | 321 | 6.6 | 146 | 668 | 94 | 3.1 | 53 | |
| 1077 | 281 | 3.4 | --- | 860 | 103 | 4.8 | 59 | |
| 1126 | 237 | 3.0 | - | 627 | 60 | 1.8 | 77 | |
| 952 | 238 | 1.9 | - | 564 | 109 | 2.6 | 63 |
* Patient taking 2 mg dexamethasone/day.
logical examination revealed pure hyperplasia of the zona fasciculata; there was no nodule formation. Crooke’s hyaline degeneration was present in the pituitary gland.
Discussion
When the patient was admitted to the Peter Bent Brigham Hospital she presented the characteristic clinical and biochemical abnormalities of disseminated adrenocor- tical carcinoma. Previous series have em- phasized that patients with adrenocortical carcinoma often present with palpable mass- es in the abdomen (7, 8). The patient also manifested a rapid downhill course with characteristic metastases to the lung and liver (8). Adrenocortical carcinoma is fre- quently characterized by markedly elevated 17-ketosteroid excretion, the levels in our patient approximating 250 mg/24 hr at a time when her disease was widely met- astatic. It is also known that adrenocortical carcinoma is often characterized by the increased urinary excretion of various cor- tisol precursors. Tetrahydro-S, pregnanet- riol and dehydroepiandrosterone excretion rates are commonly elevated in adrenocor- tical carcinoma and this point has been a useful differential feature suggesting the presence of a carcinoma (9). The patient presented in this report similarly mani- fested increased urinary intermediate me- tabolite excretion values consistent with multiple hydroxylase defects. The tetra-
hydro compound S excretion rate was three times normal and the pregnanetriol excre- tion was more than ten times normal, sug- gesting defects in both 11- and 21-hydroxy- lation. Estrogen and testosterone excretion rates were also elevated suggesting de novo synthesis or shunting of presursor com- pounds into these synthetic pathways in the carcinomatous tissue. Peripheral con- version to estrogen and testosterone is also possible from precursor substances pro- duced in the neoplastic tissue.
The report case departs from an other- wise characteristic presentation primarily by the duration and apparent non-auton- omous nature of what ultimately proved to be a malignant adrenal neoplasm. Nine years prior to admission, the patient was hirsute and amenorrheic; 17-KS excretion was 30 mg/24 hr. At that time, 17-OH ex- cretion was not increased, and clinically she did not manifest the clinical findings of Cushing’s syndrome. Five years prior to admission, her 17-KS excretion remained elevated but suppressed following low dose dexamethasone administration and in- creased following ACTH stimulation. At that time, there was the questioned abnor- mality of the left adrenal gland on retro- peritoneal air study. Three years prior to admission, while on prednisone therapy, 17- KS excretion suppressed to 20% of the con- trol value, again consistent with suppres- sion of steroid output. One major possibil-
ity is that a slow-growing carcinoma was present in the left adrenal gland at the on- set of this patient’s illness. It is possible that the carcinoma was making androgenic compounds sufficient to increase 17-KS ex- cretion but without elevated production of cortisol. Under these circumstances the tumor-free gland would not be suppressed. Thus, suppression of 17-KS and 17-OH ex- cretion seen after glucocorticoid adminis- tration could have reflected a change in steroid production by the tumor free gland, the tumorous tissue, or both. However, the magnitude of decline of ketosteroid excre- tion following prednisone administration (35 to 7 mg/24 hr) makes it unlikely that suppression of the tumor-free gland alone could account for the apparent suppression of ketosteroid excretion. Alternatively, the neoplasm may have been under some de- gree of physiologic control. Adrenal neo- plasms, however, are not ordinarily under the control of ACTH (10). Adrenocortical neoplasms may respond to ACTH admin- istration but suppression of steroid produc- tion following dexamethasone administra- tion is rare. Kendall and Sloop (11) have reported a patient with a virilizing adreno- cortical adenoma that demonstrated sup- pression of 17-OH excretion following low- dose dexamethasone administration. Adre- nocortical carcinomas, on the other hand, rarely stimulate with ACTH, while suppres- sion with dexamethasone must be very rare.
The other major possibility is that both glands could have been hyperplastic at the onset of the patient’s illness, with a neo- plasm as a late occurrence in the left adre- nal gland. Adrenal lesions responsive to dexamethasone and ACTH administration could include simple idiopathic hyperplasia, nodular hyperplasia, acquired adult benign androgenic overactivity or post-pubertal virilism associated with an acquired hy- droxylase deficiency. The absence of the physical findings associated with Cushing’s syndrome and steroid suppression following low-dose dexamethasone administration should exclude idiopathic hyperplasia and
nodular hyperplasia, suggesting hyperplasia possibly associated with a hydroxylase de- ficiency. The fact that the remaining right adrenal gland at autopsy weighed 20 g and revealed diffuse hyperplasia of the zona fas- ciculata supports the possibility that both glands could have been abnormal.
Several early reports suggested that adre- nal hyperplasia might be associated with neoplasia but they were not accompanied by steroid excretion data (12, 13). Hamwi et al. (14), however, reported a case similar to ours in a 39-year-old female who by his- tory had been masculinized for 30 years. Preoperatively, 17-ketosteroid excretion and pregnanetriol excretion values were markedly elevated and were responsive to ACTH stimulation and glucocorticoid sup- pression. A large adrenal tumor was sur- gically removed and was histologically iden- tified as an adrenocortical carcinoma. The contralateral adrenal gland was atrophic but postoperatively 17-ketosteroid and pregnanetriol excretion became elevated and suppressed following glucocorticoid ad- ministration. It is also of interest that, in Hutter’s series (15) of adrenocortical car- cinoma treated with ortho-para’DDD, the authors reported that at autopsy in seven cases the remaining tumor-free gland was normal in one case, atrophic in four, but in two cases was hypertrophied.
The present case, therefore, supports the possibility that adrenocortical carcinoma may arise in hyperplastic tissue subjected to chronic ACTH stimulation. If hyper- plasia does indeed predispose to malignant change, then an adrenocortical carcinoma may not arise de novo but degeneration into an invasive process could occur over time. This transition to an invasive process might occur coincident with loss of ACTH regu- lation and emergence of true autonomy.
Acknowledgments
These investigations were supported in part by the John A. Hartford Foundation, Grant 9893, and in part by USPHS Research Grant AM-5100-14 from the National Institute of Arthritis and Meta- bolic Diseases, The clinical studies were carried
PROFILE OF AN ADRENAL CARCINOMA
August 1971
out in the Clinical Research Center of the Peter Bent Brigham Hospital, supported by Grant 8- MOI-FR-31-06.
Dr. Williams is an Investigator of the Howard Hughes Medical Institute.
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