Significant Regression of the Tumor Combined with the High Level of Plasma Cortisol by Low-Dose Administration of O, p’-DDD in a Case with Cushing’s Syndrome Caused by Adrenocortical Carcinoma
KOROKU OTOKIDA, MOTOYUKI NAKAMURA, MAKOTO TAKEDA, TOSHIHARU ITO, MASATAKA KATO, TOMOYUKI MASUDA* and ATSUSHI TASHIRO*
The Second Department of Internal Medicine and *the Second Department of Pathology, Iwate Medical University School of Medicine, Morioka 020
OTOKIDA, K., NAKAMURA, M., TAKEDA, M., ITO, T., KATO, M., MASUDA, T. and TASHIRO, A. Significant Regression of the Tumor Combined with the High Level of Plasma Cortisol by Low-Dose Administration of O, p’-DDD in a Case with Cushing’s Syndrome Caused by Adrenocortical Carcinoma. Tohoku J. exp. Med., 1986, 150 (4), 407-411 - The effect of o, p’-DDD on a functioning adrenocortical carcinoma is described. A 52-year-old woman, who had a huge adrenocortical carcinoma and pulmonary metastasis, was treated by a low-dose administration of o, p’-DDD, which reduced the tumor size. The excretion of urinary 17-OHCS was decreased, whereas plasma cortisol was not decreased but rather increased. This was considered to be caused that o, p’-DDD functioned as a cytotoxic factor which did not improve the states of hyperkalemia, hyperglycemia and hypertension. This suggested that monitoring to measure multiple steroids in addition to plasma cortisol and urinary 17-OHCS was useful for recognizing the general conditions of patients with adrenocortical carcinoma receiving o, p’-DDD therapy. o, p’-DDD therapy ; functioning adrenocortical carcinoma ; 17-OHCS ; cortisol
Several reports have been made on the effect of 1-dichloro-2-(o-chlorophenyl)- 2-(p-chlorophenyl)-ethane (o, p’-DDD) in reducing adrenocortical carcinoma and cortisol secretion from the tumor cells in patients with adrenocortical carcinoma (Sheehan et al. 1953 ; Bergenstal et al. 1960; Lipsett et al. 1963; Hutter and Kayhoe 1966 ; Kelly et al. 1979 ; Naruse et al. 1984). During a long-term admin- istration of o, p’-DDD for adrenocortical carcinoma, the excretion of 17- hydroxycorticosteroid (17-OHCS) has been known to be immediately reduced followed by reduced cortisol secretion. A discrepancy between changes in the urinary level of 17-OHCS and the plasma concentration of cortisol in response to Received August 11, 1986 ; accepted for publication November 7, 1986.
o, p’-DDD-treatment has been reported on adrenocortical adenoma accompanying Cushing’s syndrome by Fukushima et al. (1971).
This paper reports the effect of o, p’-DDD on a functioning adrenocortical carcinoma which caused a high concentration of cortisol in plasma and a large amount of urinary 17-OHCS.
CASE REPORT
Clinical course
A 52-year-old woman was admitted to a hospital in January, 1984, because of edema in the lower extremities and hypertension. Although she had been suffering from hypertension for 8 years before admission, she had not received any medication. She had menopause at the age of 37 years. Severe mental depres- sion, hypokalemia and moon face developed during the admission. She was referred to our clinic for further examination and treatment, and was hospitalized on the 20 th, June, 1984.
She had reddish cheeks, moon face, truncal obesity, muscular atrophy of the extremities and edema of the lower extremities. Her weight was 51.0 kg and height was 155 cm. Blood pressure was 166/100 mm Hg, and pluse was 76/min with no arrhythmia. The pubic hair was normal. In the left abdomen, a large, rough-surface tumor of the size of an infant’s head was palpated, expanding to the abdominal midline.
Laboratory and endocrinological findings on admission
17-OHCS, 17-ketosteroid (17-KS) and 17-ketogenic steroid (17-KGS) in urine were photometrically measured. Plasma corticosteroids, ACTH and renin activ- ity were measured using radioimmunoassay techniques.
The results of the routine laboratory examinations are shown in Table 1. Hypokalemia was marked. The white blood cell count was within the normal range, although lymphocytopenia was present. Lactic dehydrogenase (LDH), alkaline phosphatase and total cholesterol were elevated in serum. Fasting blood sugar was 225 mg/100 ml, requiring insulin injection. Analysis of arterial blood gas showed a remarkable metabolic alkalosis at pH 7.486, 40.4 mm Hg of pCO2 and 30.3 mEq/liter of HCO3.
The endocrinological examinations indicated a high plasma cortisol level (Table 2) without a circadian rhythm. Excretions of 17-OHCS and 17-KS in urine were also elevated (Table 3). The level of cortisol in plasma remained elevated under either low or high dexamethasone-suppression. Dehydroepian- drosterone sulphate was increased in plasma, suggesting that Cushing’s syndrome was caused by adrenocortical carcinoma. Testosterone, estradiol and aldosterone levels in plasma were always within normal ranges. The plasma deoxycorticos- terone level was increased.
| Blood chemistry | Blood picture | ||
|---|---|---|---|
| Total protein | 5.5 g/100 ml | WBC | 6800 /mm3 |
| Albumin | 3.52 g/100 ml | Baso. | 0 % |
| Total bilirubin | 0.4 mg/100 ml | Eosin. | 0 % |
| Glucose | 225 mg/100 ml | Neutro. | 91 % |
| GOT | 17 IU | Lymph. | 4 % |
| GPT | 15 IU | Mono. | 4 % |
| LDH | 1012 U | RBC | 453 ×104/mm3 |
| (Wroblewski) | Hb | 12.7 g/100 ml | |
| Alkaline phosphatase | 18.3 U (K.A.) | Ht | 38.1% |
| Platelets | 18.6×104/mm3 | ||
| Na | 144.8 mEq/liter | ||
| K | 2.5 mEq/liter | ||
| CI | 101.1 mEq/liter | ||
| BUN | 10.6 mg/100 ml | ||
| Creatinine | 0.7 mg/100 ml | ||
| Total cholesterol | 336 mg/100 ml |
| Cortisol | 42.7 mg/100 ml |
| 11-Deoxycortisol | 16.4 ng/ml |
| Aldosterone | 68 pg/ml |
| Corticosterone | 3.53 ng/ml |
| 11-Deoxycorticosterone | 832 pg/ml |
| Progesterone | 1.5 ng/ml |
| Teststerone | 121.6 ng/100 ml |
| DHEA | 3.9 ng/ml |
| DHEA sulphate | 4210 ng/ml |
| Renin activity | 24.58 ng/ml/hr |
| ACTH | 10 pg/ml |
DHEA, Dehydroepiandrosterone
| Tetrahydro S | 3.92 mg/day |
| 17-OHCS | 16.7 mg/day |
| 17-KS | 15.11 mg/day |
| 11-Deoxy-17-KGS | 7.2 mg/day |
| 11-Oxy-17-KGS | 36.9 mg/day |
| Adrenaline | 0.5 µg/day |
| Noradrenaline | 6.0 µg/day |
Radiographic findings
A chest x-ray film showed a small round shadow, which was 2×2 cm in size and accompanied no “silhouette sign”, in the left lower pulmonary field, suggest- ing a metastatic pulmonary carcinoma (Fig. la). At abdominal x-ray examina- tion, many calcifications were found to be scattered in a huge tumor in the left upper abdominal quadrant. Computed tomographic scan revealed a huge tumor, which was 15x20 cm in size, with calcifications in the region from the left peritoneal to the retroperitoneal space (Fig. 2). Ultrasonic echo examination confirmed the computed tomographic findings. However, adrenal scintigram using 131I-adosterol did not show any tumorous shadow, because the adrenal tumor
a
b
was too large to accumulate 131I-adosterol.
Clinical course and treatment
From these results, the diagnosis was made as Cushing’s syndrome due to adrenocortical carcinoma. Intravenous infusion of potassium chloride for hypo- kalemia and subcutaneous injection of insulin for high blood sugar were immedi- ately begun. And she received 0.5 g of o, p’-DDD every day from the 17th, July, 1984. After the one-week treatment, the dose was gradually increased to 2.0 g/ day in one month (Fig. 3), and the pulmonary metastatic shadow disappeared (Fig. 1b). By abdominal palpation the adrenal tumor was recognized to be regressed in size. An operation to remove the huge tumor from the abdominal cavity was decided not to be performed, because invasion into the surrounding organs was presumed in addition to pulmonary metastasis. Oral administration of o, p’-DDD was continued and the dose was increased to 3.0 g 3 months after admission.
By o, p’-DDD administration, urinary 17-OHCS was decreased to 20-50% as compared to that before the treatment. However, plasma cortisol level remained unchanged or slightly increased. The level of 17-KS in urine also continued to elevate during administration of o, p’-DDD. No improvement of hypokalemia and diabetic state was observed.
In September, 1984, the patient complained of fatigue and severe anorexia. High blood pressure continued in the range from 200/130 to 160/90 mm Hg, although potent antihypertensive agents were given. Plasma renin activity, which was extraordinarily high before administration of o, p’-DDD, decreased
70
Urinary 17 OHCS
and 17 KS (0-0) ( mg/day )
Plasma cortisol (pg/100 ml ) (4-4)
60
50
50
40
40
30
30
20
10
0
o, p’-DDD (g/day )
3
o,p’-DDD (g/day)
Plasma renin activity (ng/ml/hr)
25
64.3
20
15
10
Renin
5
0
Jul
Aug
Sep
Oct
Nov
a
b
following the regression of the abdominal tumor (Fig. 3).
Dyspnea developed with cough and sputum on the 15th, October, 1984. A chest x-ray film revealed shadows of pneumonia in the right upper pulmonary field. However, her consciousness deteriorated and dyspnea was exacerbated. She died on the 2nd, November, 1984.
Pathological findings of the tumor
Autopsy was done 2 hr after death. A large tumor, which measured 20× 16 x 8 cm in size and 1200 g in weight, occupied the left part of the abdominal cavity (Fig. 4a). The cut surface of the tumor was yellowish-white in color, although necrotic and hemorrhagic lesions or whitish fibrous proliferations were seen (Fig. 4b). The right adrenal gland was atrophic and weighed 1 g (inset in Fig. 4a). Microscopical examination showed the tumor cells consisted of markedly atypial cells including bizarre nuclei, revealing the adrenocortical carcinoma.
DISCUSSION
Several investigators have reported that o, p’-DDD is effective against adrenocortical carcinoma, complete surgical removal of which is not expected (Sheehan et al. 1953; Bergenstal et al. 1960; Lipsett et al. 1963; Hutter and Kayhoe 1966 ; Kelly et al. 1979 ; Naruse et al. 1984).
After administration of 2.0 g/day of o, p’-DDD for a month as presented herein, the abdominal tumor of our patient significantly regressed in size.
In patients with pituitary Cushing’s syndrome, Bledsoe et al. (1964) reported a decrease in urinary 17-OHCS without a decrease of either plasma 17-OHCS or cortisol by administration of o, p’-DDD. They concluded that o, p’-DDD has a potent influence on extra-adrenal metabolism, and causes a decrease in urinary excretion of tetrahydrocortisol and tetrahydrocortisone which occupy a large portion of 17-OHCS, because o, p’-DDD converts cortisol to 6-hydroxycortisol which is not regarded as a urinary 17-OHCS.
Fukushima et al. (1971) investigated the effect of o, p’-DDD on cortisol metabolism in 6 patients. Cortisol secretion was increased in a patient with metastatic adrenal tumor and patient with hepatoma, while it was decreased in 2 other patients, one of whom had Cushing’s syndrome with bilateral adrenal hyperplasia. In the latter 2 patients, the effect of o, p’-DDD was obscure. Although the results seemed to be contradictory, these suggested that the treat- ment with o, p’-DDD produced different responses of cortisol secretion as a conse- quence of a number of metabolic factors which could not discerned in the study.
In the present case, hypertension, hypokalemia and diabetic state were not improved regardless of intensive therapy with antihypertensive agents, insulin and infusion of KCI. It has been reasoned from this phenomenon that a large amount of cortisol was being secreted from the primary tumor itself of the adrenal gland.
The significant increase of plasma renin activity is thought to be a probable result of renal ischemia due to stretch or stenosis of the renal artery being compressed by the adrenal tumor. An evidence for this is the decrease of renin activity after the regression of the adrenal tumor was confirmed on palpation during o, p’-DDD therapy.
Hutter and Kayhoe (1966) reported the result of o, p’-DDD therapy in 138 patients with adrenocortical carcinoma. Significant regression of adrenocortical carcinoma was recognized in 59 of them. In 2 cases, pulmonary metastasis disappeared in 4-6 weeks by o, p’-DDD therapy. The average dose of o, p’-DDD to decrease the size of adrenocortical carcinoma was 8.1 g, and the mean duration of regression was 10.2 months. However, the regression of adrenocortical car- cinoma was not always correlated with the reduction of urinary corticosteroid excretion during o, p’-DDD therapy.
In this case, a small dose of 0.5 g of o, p’-DDD was given daily, because her general condition was so severe that an intensive o, p’-DDD therapy might become lethal. The dose of o, p’-DDD was finally increased to 3.0 g daily, although it was still a small dose (Sheehan et al. 1953; Bergenstal et al. 1960; Lipsett et al. 1963 ; Hutter and Kayhoe 1966; Kelly et al. 1979; Naruse et al. 1984). As shown in Figs. la, b, a round pulmonary metastatic shadow disappeared at two months in o, p’-DDD therapy. Besides a definite regression of primary tumor was observed from a huge mass (20x15×20 cm) calculated by the abdominal CT pictures before the start of o, p’-DDD, to an about half-sized tumor (16x8x 20
cm) directly measured on the autopsy.
Our patient showed many unfavorable fiindings of high blood pressure, hypokalemia, hyperglycemia and hypercortisonemia which did not cease during o, p’-DDD therapy. Whereas, the drug was much effective on reduction of a primary abdominal carcinoma in size, disappearence of the metastatic pulmonary tumor and decreasing excretion of urinary 17-OHCS. Such dissociation was also reported by Kelly et al. (1979) that a corticosteroid response could not be correlat- ed with increased survival rate of patients with adrenal carcinoma treated with o, p’-DDD.
The result provokes to establish the treatment method whether it is much effective to employ a low dose or a high dose of o, p’-DDD to be administered to patients with adrenocortical carcinoma. Its high dose therapy has an inhibitory action on both adrenal tumorous mass and hypercortisonemia, although acute adrenal insufficiency accidentally happens into lethal states of patients. On the other hand, there is a possibility that some other steroids hypersecreted from adrenocortical carcinoma bring about hypokalemia and high blood pressure partially or totally, for an example, as herein indicated the high level of plasma 11-deoxycorticosterone which is a potent mineralcorticoid. Kelly et al. (1979) demonstrated that measuring multiple steroids was helpful for monitoring the response to o, p’-DDD administration in 4 patients with adrenal carcinoma.
Attempts have been directed toward an establishment of o, p’-DDD treatment against adrenocortial carcinoma, preventing from serious side effects by monitor- ing some corticosteroids in addition to cortisol in blood, and adjusting a sufficient amount of o, p’-DDD (Bergenstal et al. 1960; Kelly et al. 1979 ; Naruse et al. 1984).
References
1) Bergenstal, D.M., Hertz, R., Lipsett, M.B. & Moy, R.H. (1960) Chemotherapy of adrenocortical cancer with o, p’-DDD. Ann. intern. Med., 53, 672-682.
2) Bledsoe, T., Island, D.P., Ney, R.L. & Liddle, G.W. (1964) An effect of o, p’-DDD on the extra-adrenal metabolism of cortisol in man. J. clin. Endocr., 24, 1303-1311.
3) Fukushima, D.K., Bradlow, H.L. & Hellman, L. (1971) Effects of o, p’-DDD on cortisol and 6-hydroxycortisol secretion and metabolism in man. J. clin. Endocr., 32, 192-200.
4) Hutter, A.M. & Kayhoe, D.E. (1966) Adrenal cortical carcinoma. Results of treat- ment with o, p’-DDD in 138 patients. Amer. J. Med., 41, 581-592.
5) Kelly, W.F., Barnes, AJ., Cassar, J., White, M., Mashiter, K., Loizou, S., Welbourn, R.B. & Joplin, G.F. (1979) Cushing’s syndrome due to adrenocortical carcinoma. A comprehensive clinical and biochemical study of patients treated by surgery and chemotherapy. Acta endocr., 91, 303-318.
6) Lipsett, M.B., Hertz, R. & Ross, G.T. (1963) Clinical and pathophysiologic aspects of adrenocortical carcinoma. Amer. J. Med., 35, 374-383.
7) Naruse, T., Koike, A., Kato, K., Ishii, T., Suzumura, K. & Matsumoto, K. (1984) Adrenocortical carcinoma responded to treatment with o, p’-DDD — A case report. Endocr. jap., 31, 417-426.
8) Sheehan, H.L., Summers, V.K. & Nichols, J. (1953) D.D.D. therapy in Cushing’s syndrome. Lancet, 1, 312-314.