Adrenocortical Carcinoma Responded to Treatment with O,p’-DDD -A Case Report-
TAKAYOSHI NARUSE, AKIHIKO KOIKE, KENICHI KATO, TOSHIAKI ISHII, KAZUYOSHI SUZUMURA AND Kozo MATSUMOTO
The 1st Department of Surgery, Aichi Medical University, Yazako, Nagakute, Aichi-gun, Aichi 480-11
Abstract
A case of a huge inoperable adrenocortical carcinoma which secreted testo- sterone without characteristic symptoms was treated with o,p’-DDD (2,2-bis (2-chlorophenyl-4 cholorophenyl) 1,1-dichloroethane). With this therapy, the tumor decreased in size which was confirmed by the computed tomography (CT). Eighteen months later, however, lethargy and logopathy appeared and the tumor grew again rapidly with the withdrawal of o,p’-DDD performed for the evaluation of these mental disturbances. The tumor then diminished gradually in size soon after the treatment was resumed and the above un- favorable symptoms were not developed again with the combined administration of a central nervous stimulant.
During o,p’-DDD treatment, plasma testosterone and estrogen decreased, and plasma aldosterone also decreased but within the normal range. Plasma cortisol also tended to decrease despite hydrocortisone was administered. Plasma adrenocorticotropic hormone (ACTH) was maintained within the normal range for the first six months but then increased gradually. It decreased and became normal with the additional administration of hydrocortisone.
The patient’s normal menstruation at the preadministrative stage changed to oligomenorrhea, then amenorrhea after the treatment, but no endocrinologi- cal sign except for the menses was observed during the treatment.
The best treatment for an adrenocortical tumor is the surgical excision of the primary lesion regardless of the hormone production. However, when the tumor is inoperable due to its invasion of the surrounding tissues or metastases and secretes steroids with biologi- cal activity, a pharmacotherapy is usually applied to treat the tumor and distinct metastases. As drugs for this medicinal therapy, there have been many agents such as aminogluthetimide, trilostane and o,p’-
DDD. Among them, o,p’-DDD has both cytotoxic action for the adrenal cortex (Nelson et al., 1949) and steroid bio- synthesis-blocking action for the adrenal cortex (Ojima et al., 1981) although the others have only the latter action. The former action is considered to be effective against the tumor even if it does not secrete hormone.
O,p’-DDD, discovered by Nelson et al., in 1949 as an agent having cytotoxicity for the adrenal cortex of the dog, was first clinically used by Bergenstal et al., in 1960 in a case of adrenocortical cancer which
developed distant metastases after the re- moval of the primary lesion. Hutter et al., 1969, investigated 138 cases of adrenocorti- cal cancer treated with o,p’-DDD, and re- ported its value in clinical use.
In Japan, 104 cases of adrenal diseases including ours treated with this agent had been reported up to November, 1983 (Shimizu et al., 1983). They consisted of 82 cases of Cushing’s syndrome (44 of Cushing’s disease, 7 of adrenal adenoma, 23 of adrenal carcinoma and 8 of others), 10 cases of adrenal carcinoma producing hormones except for cortisol, and 12 cases of non-functioning adrenal carcinoma. Among these cases of adrenal carcinoma, in all surviving cases except for the present case the primary tumors were resected, and o,p’- DDD was prescribed for the distant metas- tases. In the present case, primary lesion was not able to be resected and o,p’-DDD was administrated for the primary tumor. There has been no literature in Japan de- scribing the effects of this agent on the primary tumor of adrenocortical carcinoma.
This report presents the clinical course of the patient, changes in the plasma con- centrations of the adrenocortical steroids and ACTH during the course, and matters that require special attention in relation to the administration of o,p’-DDD.
Materials and Methods
Case presentation
The patient, a 44-year-old Japanese female, was aware of slight right upper abdominal pain in August, 1981. She was diagnosed as having a hepatoma after emergent sonography and a CT-scan given by her family physician. The case was then referred to Aichi Medical Univer- sity Hospital for further evaluation and treatment in September, 1981.
She has no family history or anamnesis of endocrinologial disease. Her menstruations were regular and normal in volume, but she had never been pregnant. The results of a physical ex- amination given on admission revealed normal stature and mental state without moon face or buffalo hump. The blood pressure was 130/88 mmHg with a regular pulse rate of 72 per minute and a body temperature of 36.1℃. Hair growth of both the head and pubic region looked nor- mal. In the right hypochondrium, a fist-sized tumor like an enlarged liver was detected with no other particular abdominal findings.
Laboratory and endocrinological data on admission
All blood samples for data were taken during fasting early in the morning. Complete blood count (CBC) and blood chemistry were normal except for serum lactic dehydrogenase (LDH) (Tab. 1). The results of a 50 gm oral glucose tolerance test revealed normal patterns of both blood glucose and serum immunoractive insulin. Daily urinary output was also normal and there
| C. B. C. | Blood Chemistry | Isozyme of LDH | ||
|---|---|---|---|---|
| WBC | 6500/mm3 | Total protein | 6.6 g/100 ml | Li 15.5% |
| RBC | 398×104/mm3 | Albumin | 3.7 g/100 ml | L2 27.0% |
| Hb | 10.0 g/100 ml | Total bilirubin | 0.43 mg/100 ml | L: 24.3% |
| Ht | 29.6% | Direct bilirubin | 0.21 mg/100 ml | L+ 17.1% |
| Thrombocyte | 31.4×104/mm3 | Glucose | 90 mg/100 ml | L5 16.1% |
| GOT | 19 mU/ml | |||
| GPT | 10 mU/ml | |||
| Alkaline phosphatase | 160 mU/ml | |||
| Lactic dehydrogenase | 524 mU/ml | |||
| Choline esterase | 0.62 4pH | |||
| Na 141 mEq/L | ||||
| K 4.1 mEq/L | ||||
| Cl | 104 mEq/L | |||
| Plasma ACTH | 87 | pg/ml | Blood adrenalin | 13 pg/ml | |
| Plasma cortisol | 23.5 | µg/100 ml | Blood noradrenalin | 107 pg/ml | |
| Plasma | aldosterone | 10.0 ng/100 ml | Urinary 17-OHCS | 2.4 mg/day | |
| Plasma | testosterone | 93 | ng/100 ml | Urinary 17-KS | 4.7 mg/day |
| Plasma estron | 68 | ng/100 ml | Urinary aldosterone | 2.3 µg/day | |
| Plasma estradiol | 19 | pg/ml | Urinary VMA | 7.4 mg/day | |
| Plasma estriol | below 10 pg/ml | ||||
were no abnormal urinalytic findings. The re- sults of endocrinological studies revealed normal plasma concentrations of adrenocortical steroids except for testosterone, and normal urinary ex- cretion of 17-OHCS and 17-KS (Tab. 2).
Radiographic and imaging findings on admission
Radiographic and electrocariographic findings for the chest were normal. The upper gastro- intestinal series of radiography revealed no ab- normality. However, a palpable tumor was identified in the right upper quadrant with ab- dominal CT-scan, and measured 10×9 cm (Fig. 1). The tumor seemed to be developing in the right lobe of the liver.
Surgery
Based on these findings, this tumor was sus- pected to be an asymptomatic testosterone producing neoplasm developing from the right adrenal gland into the right lobe of the liver. Laparotomy performed in September, 1981, con- firmed that the tumor was an adrenal carcinoma. The total excision of the tumor was impossible because it had already invaded the liver and in- volved the vena cava. However, no hepatic metastases or peritoneal implants were observed. A biopsy was taken from the tumor for a histo- logical examination.
Histological findings
The histological diagnosis of the biopsy was an adrenocortical carcinoma, the cells of which showed a sheet-like or alveoli-like pattern and mixed in some parts with relative atypical ge- mistcytic or poly-nuclear cells (Fig. 2). A few mitotic features were also seen. There were small vessels between the medullary growing tumor cells, but no distinct sign of invasion of the vessel’s wall by tumor cells was observed.
Results
Treatment and clinical course
Initially, 60Co irradiation was employed, but the tumor grew during the irradiation and right hypochondralgia increased with nausea and anorexia. This irradiation was concluded to be ineffective when 5000 rads were irradiated. The largest plane of the tumor then shown by CT-photogram was
almost the same in size as that shown by previous photogram. Then the patient was placed on a 1.5 gm a day dose of o,p’-DDD (December, 1981). The dose was increased to 4.5 gm a day after confirming that it had no acute side effect. Simultaneously, hydrocortisone, 20 mg a day, was administ- rated to prevent adrenal insufficiency that may arise from the administration of o,p’- DDD.
The general condition of the patient gradually improved following the administ- rations of o,p’-DDD. A week later, nausea, anorexia, and pain noticed during the irra- diation disappeared. The tumor became smaller and impalpable two months later (February, 1982). The plane size of the tumor then measured by CT-scan was un- expectedly found to be unchanged, but the three dimensionally estimated volume de- creased remarkably. The patient was then
switched to the outpatient clinic at the end of February, 1982. Since then, the patient has lived without any complaint related to the tumor for over one year. For this period the tumor remained impalpable and the volume on CT-photograms also decreased gradually. No metastasis to the other ad- renal gland was noticed detected by these CT-photograms.
In April, 1983, 18 months after the start of o,p’-DDD therapy, the patient manifested lethargy and logopathy which were gradually progressive and was readmitted to the hos- pital. The results of both CT-scan of the brain and cerebral angiography taken showed the size of the sella turcia to be normal and showed no metastatic foci in the brain. Electroencephalogram (EEG) revealed fre- quent beta waves superimposed on slow alpha and theta waves that were regarded as a side effect of the drug.
The withdrawal of o,p’-DDD clearly alleviated the abovementioned mental dis- turbance within a few days, although hydro-
cortisone increased to 50 mg a day had no effect. However, the withdrawal of this agent resulted in a rapid increase in the size of the clinical tumor and in pain. The volume of the tumor then measured on CT- photogram was seen to have increased.
In such a context, o,p’-DDD, 4.5 gm a day, and hydrocortisone, 50 mg a day, were resumed concurrently with the administration of Citicoline, 600 mg a day. The increase in the size of the palpable tumor stopped two weeks later and a pain in the hypo- chondrium was relieved soon. However, the rapid decrease seen following the first ad- ministration of o,p’-DDD was not observed. At this time, no unfavorable symptom deve- loped clinically while EEGs were the same as the previous ones. The changes in ab- dominal findings corresponding with tumor volume and clinical signs are shown in Fig. 3.
The patient’s menstruation, being regular until laparotomy, became irregular and oli- gomenorrhea and finally amenorrhea six months later. After the resumption of the
gm
o.p’-DDD
1.5
o.p’-DDD
3.0
4.5
60 Co
5000
rad
Anorexia
Pain
·lethargy
logopathy
Abd. finding
Tumor volume
2000
1000
cm
3
Ope
81
‘82
83
11
12
1
2
5
8
10
2
5
7
9
11
0. P’-DDD 4.5gm/day
Hydrocortisone 20mg/day
Hydrocortisone 50mg/day
RBC ( × 104)
500
400
A
A
A
A
A
A
A
A
300
A
4
4
4
A
WBC
8000
A
6000
4000
2000
Serum Na (mEq/L)
140
130
120
Serum K (mEq/L)
6
4
2
Serum LDH (mU/mL)
800
X
600
X
400
×
X
200
X
X
S-GPT (mU/mL)
40
20
S-GOT (mU/mL)
40
20
‘81
82
83
11
1
3
5
7
9
11
1 3 5 7 9 11
normal range
0. P’ -DDD 4.5gm/day
Hydrocortisone 20mg/day
Hydrocortisone 50mg/day
Plasma testosterone (ng/100ml)
100
50
Plasma estrogen (pg/mL)
100
4-A Estron (normal range : 31~143)
Estradiol( normal range : 34~252)
Estriols were always undetectable
50
Plasma aldosterone (ng/100ml)
10
5
Plasma ACTH (pg/mL)
700
400
100
Plasma cortisol ( µg/100ml)
20
10
☐
Urinary 17-OHCS & 17-KS (mg/day)
10
17-OHCS(normal range 1.9~6.1)
17-KS (normal range 3.1~8.8)
5
Tumor volume (cm3)
2000
1000
‘81
82
83
11
1
3
5
7
9
11
1
3
5
7
9
11
| Time | Plasma cortisol (mg/100 ml) | Plasma ACTH (pg/ml) | ||||
|---|---|---|---|---|---|---|
| November '81 | November '82 | May '83 | November '81 | November '82 | May '83 | |
| 6.00 | 4.5 | 4.6 | 3.3 | 77 | 753 | 295 |
| 12.00 | 40.2 | 47.9 | 3.8 | 130 | 1016 | 790 |
| 18.00 | 20.0 | 11.0 | 4.2 | 100 | 716 | 580 |
| 24.00 | 4.5 | 4.6 | 4.2 | 70 | 743 | 670 |
therapy, no hypercortisolistic sign has been noticed at this writing even with the addi- tional administration of hydrocortisone.
Laboratory and endocrinological data during the course
CBC and blood chemistries except for LDH remained within the normal range (Fig. 4). LDH corresponded with the tumor volume. The plasma aldosterone concent- ration also remained within the normal range. Both plasma testosterone and plasma estrogen gradually decreased (Fig. 5).
Plasma cortisol decreased slightly for the first six months and was then elevated for the following three months. After that, it again decreased until the development of the mental disorders (i.e. until the additional administration of hydrocortisone) (Fig. 5). Diurnal rhythm of plasma cortisol was pre- served until the development of the mental disorder, and then lost (Tab. 3). Plasma ACTH was normal for the same first six months as was plasma cortisol, and increased from then. The rising level of plasma ACTH did not soon drop after the addi- tional administration of hydrocortisone but had dropped to the normal range at the time of writing (Fig. 5). The diurnal rhythm of plasma ACTH remained normal (Tab. 3).
Discussion
Adrenocortical carcinoma is so rare that only one case is found in half a million of the population (Nelson et al., 1949, Vilar
et al., 1959). This carcinoma is also reported to be a highly malignant neoplasm resulting in short life expectancy (Huvos et al., 1970, Lipsett et al., 1963, MacFarlane et al., 1958). Several investigators reported the effect of o,p’-DDD (Hutter et al., 1966, Lubitz et al. 1973) and emphasized that this therapy led to prolonged survival only in cases with metastases after the resection of the primary tumor (Lubitz et al., 1973). The mean survival period for inoperable cases has been reported to be 8.4 months (Hutter et al., 1966). Among the Japanese cases of adreno- cortical cancer treated with o,p’-DDD, 14 inoperable cases were reported to have a shorter surviving period until death than the other 28 operable cases (Shimizu et al., 1983). Our case may be one of the longest surviv- ing inoperable cases treated with o,p’-DDD alone in Japan.
Previous investigators estimated the effect of o,p’-DDD with urinary and/or the plasma steroid level, measurable parameters and overall clinical response. With the recent progress in imaging techniques, the measure- ment of the size of the tumor has become easy. Among them, CT-scan is one of the best methods to use in determining the size of the tumor. However, in the present case, strangely the largest planes of the tumor calculated by CT-photograms were not so changed or coincided with the changing clinical size. In contrast, the volume of the tumor integrated three dimensionally on CT- photograms was changed with the clinical features of the tumor (Fig. 4). This is be- cause the tumor was developed craniocaudally
instead of horizontally. On the assessment of the tumor’s response to the chemotherapy, at present, the effect of a drug is estimated by the change in the largest plane of the tumor shown by the CT-photogram. On the basis of our experience, however, we recom- mended the volume estimation in a case with a huge solid tumor.
Endocrinologically, the plasma testo- sterone before treatment was produced presumably by the tumor and the decrease in the amount of testosterone produced verified the effect of o,p’-DDD on the tumor. Plasma cortisol production also decreased gradually while hydrocortisone had been concurrently administered. The tran- sient elevation of plasma cortisol was pre- sumably caused by the increase in plasma ACTH because this increase in plasma ACTH started at this time and was probably due to hypocortisolism caused by the administ- ration of a small amount of hydrocortisone. The reason for which the plasma cortisol again decreased despite the plasma ACTH increase after that was probably the pro- gressive damage to the normal adrenal cortex. In spite of the additional administration of hydrocortisone, 50 mg a day, plasma ACTH did not fall to the normal range. This might be due to a hyperplastic change in the pituitary gland for longstanding low grade hypocortisolism. The plasma ACTH has been decreasing and had become normal by the time of writing. We know that a patient on treatment with o,p’-DDD requires more hydrocortisone than is usually required (20 mg a day) after bilateral adrenalectomy.
In contrast, the plasma aldosterone sup- posed to be secreted from the normal ad- renal cortex maintained its normal level. Ojima et al., 1981, proved that o,p’-DDD had an inhibitory action on desmolase, 33- hydroxysteroid dehydrogenase, 21a-hydroxy- lase and 118-hydroxylase in the adrenal cortex. They also observed an decrease in
plasma aldosterone induced by o,p’-DDD. However, the maintenance of the plasma aldosterone, as in onr case, was reported by Temple et al., 1969. It is strongly suspected that o,p’-DDD has a different action on the biosynthesis of cortisol from that of aldo- sterone.
As the side effects of o,p’-DDD, many unfavorable symptoms such as gastrointesti- nal disturbance, central nervous disturbance, rash on the skin, gynecomastia and arthral- gia have been reported (Hutter et al., 1966, Lubitz et al., 1973). In 1970, we also ob- served such side effects (Naruse et al., 1970). Fortunately, in the present case o,p’-DDD could be orally taken without any gastro- intestinal discomfort. Lethargy and logo- pathy noticed eighteen months later were first considered to be due to hypocortisolism because plasma ACTH was elevated but the additional administration of the glucocorti- coid did not alleviate them. Based on this fact and findings on EEG, we concluded that they were side effects of o,p’-DDD.
With the withdrawal of o,p’-DDD, the tumor’s size was increased rapidly and even when the treatment was resumed, it was not any more effective than the previous one. Although many patients had been well controlled with o,p’-DDD, they died within a short time after the withdrawal of the drug even though its administration was later resumed (Shimizu et al., 1983). The reason for this may be a change in the malignancy of the tumor cells, a change in its sensitivity to o,p’-DDD, or changes in the defence mechanism of the host. All of these problems remain to be solved in future studies. Our experience tells us that the o,p’-DDD therapy should be persevered with and that the side effects of the drug should be relieved with other treatment combined with o,p’-DDD, and not by withdrawing the drug.
References
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