Departments of Medicine and Surgery”, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 OHS
CUSHING’S SYNDROME DUE TO ADRENOCORTICAL CARCINOMA - A COMPHRENSIVE CLINICAL AND BIOCHEMICAL STUDY OF PATIENTS TREATED BY SURGERY AND CHEMOTHERAPY By W. F. Kelly, A. J. Barnes, J. Cassar, M. White, K. Mashiter, S. Loizou, R. B. Welbourn* and G. F. Joplin
ABSTRACT
Four post-menopausal women had Cushing’s syndrome due to adrenal cortical carcinomas. Comprehensive analyses of blood and urinary steroids showed that although the steroid profiles differed between patients, the pattern in each patient remained almost constant as the disease progres- sed, or remitted due to therapy. Elevations of serum testosterone and oestradiol were commensurate with the extent of virilisation, and the urinary output of aldosterone was associated with the severity of hyper- tension. A new finding was that all had substantially increased urinary free deoxycorticosterone. Complete surgical removal of the primary tu- mours was impossible but when most of the tumour tissue was removed, full clinical and biochemical remissions were obtained for a short time in 2 patients. One patient obtained a clinical and biochemical remission from op’DDD. In another patient the drug caused reduction both in blood pressure and in urinary aldosterone excretion, but there were unpleasant side effects. A third patient could not tolerate op’DDD. Metyrapone therapy produced neither clinical nor biochemical improvement in 3 patients. The mean duration of survival was 17 months after the first symptoms and 10 months from the date of operation. Despite advances in drug therapy, adrenal cortical carcinoma remains a lethal disease. Biochemical screening of multiple steroids offers a means of early dia- gnosis and disease monitoring. Extensive surgical removal of the tumour offers the best chance of a clinical and biochemical remission.
Primary carcinoma of the adrenal cortex is extremely rare, affecting only 2 people per million. Most published data concern isolated case reports, although there have been some large series, usually assembled from multiple sources (MacFarlane 1958; Hutter & Kayhoe 1966a). The disease is usually swiftly fatal, and the diagnosis is suggested by the rapid onset of Cushing’s syndrome with elevated cortisol and suppressed plasma ACTH concentrations. The im- portant differential diagnosis is from Cushing’s syndrome due to an adrenal adenoma, which has an excellent prognosis after the removal of the tumour. One of us has operated on 9 such patients without mortality, and the first 6 (Welbourn et al. 1971) are now alive and well from 10 to 23 years after opera- tion.
Treatment of adrenal cortical carcinoma is by complete removal of the primary tumour, and by giving drugs such as op’DDD where further opera- tions are not feasible (Montgomery & Welbourn 1975). Chemotherapy of adrenal carcinoma was introduced following an observation by Nelson & Woodard (1949) that the insecticide DDT caused necrosis of the adrenal cortex in dogs. This led to purification of the compound op’DDD (ortho-para prime DDD) i. e. 1-1 dichloro-2-(0-chlorophenyl)-2-(p-chlorophenyl)-ethane, which had been present in small amounts in the original insecticide. Trials in man (Bergenstal et al. 1960; Montgomery & Welbourn 1965; Hutter & Kayhoe 1966b) demonstrated examples of regression of metastases, necrosis of adrenal tumours, and decrease in urinary steroid metabolites. Later, metyrapone was found to inhibit steroid 118-hydroxylase, and thus curtail the conversion of 11-deoxy- cortisol to cortisol, and deoxycorticosterone to corticosterone (a precursor of aldosterone) (Liddle 1974). Since cortisol and aldosterone are more potent bio- logically on a molar basis than their precursors, enzyme inhibition may be clinically useful.
Formerly, biochemical assessments of adrenal carcinoma and its response to treatment were based on non-specific urinary metabolites such as 17-oxogenic and 17-oxosteroids, but specific and sensitive assays for steroids in blood and urine are now available, and enable us to define in detail the pattern of steroids excreted.
We therefore report 4 recent patients of our own with multiple endocrine investigations to define the metabolic pathways leading to the synthesis of cor- tisol, aldosterone and the sex hormones, initially and after surgical procedures and chemotherapy with op’DDD and metyrapone. All patients were followed with serial measurements in which the same laboratory methods were used.
METHODS
Hormone measurements
Normal ranges are shown in Table 1. The following methods were used:
Serum (or plasma) cortisol. - Murphy (1967); 11-deoxycortisol (compound S): as cortisol, except for additional extraction with dichloromethane and carbon tetrachlo- ride; testosterone: Kjeld et al. (1976a); oestradiol-17: Kjeld et al. (1976b); luteinizing hormone (LH): Marshall et al. (1972); deoxycorticosterone (DOC): Cope & Loizou (1975) and aldosterone (Cope & Loizou 1973). Plasma ACTH was measured by Dr. L. Rees and 17 a-hydroxyprogesterone by Dr. G. Groom.
Urine. - Free cortisol: Beardwell et al. (1968); the inhibition of binding relative to cortisol in this assay is: 11-deoxycortisol 90 %, DOC 48 %, cortisone 17 % and testosterone 11 %; free DOC (Cope & Loizou (1975); total aldosterone: Cope & Loizou (1973); 17-oxogenic steroids (17-OGS) and 17-oxosteroids (17-OS): Medical Research Society Committee (1963); pregnanetriol: Fotherby & Love (1960).
Stimulation tests
“Synacthen Depot” (CIBA Laboratories) 1 mg im daily for 2 days; gonadotrophin releasing hormone (GnRH) 100 ug iv with measurements of LH at zero, 30 and 60 min; chorionic gonadotrophin (“Gonadotraphon LH”, HCG, Paines & Byrne Ltd), 2000 units im daily for 2 days with blood samples for cortisol, testosterone and oestradiol for a further 2 days; metyrapone (“Metopirone” CIBA Laboratories) 750 mg orally every 4 h for 24 h with measurements of urine 17-OGS and serum 11-deoxy- cortisol.
Suppression tests
Dexamethasone 2 mg orally 6 hourly for 72 h, with measurements of urine free cortisol and 17-OGS over the last 48 h.
RESULTS
Patient 1
This 59 year old lady was first investigated by us in March 1975. Typical clinical signs of Cushing’s syndrome (with only mild hirsutism) had developed during the previous 13 months, and her blood pressure was 140/100. She had had no treatment whatsoever.
Biochemistry (Table 1)
There were increased concentrations of serum cortisol, and plasma ACTH was suppressed. Plasma 11-deoxycortisol was increased basally, with a 4-fold rise one day after metyrapone. Serum testosterone was increased to that of nor- mal adult males, and there was also a large increase in serum oestradiol; serum LH was undetectable both basally and after GnRH. HCG caused no further
| Patients | Normal range2) | ||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | ||
| Blood | |||||
| a) Steroids and hormones | |||||
| Cortisol (nmol/1) | |||||
| 09.00 | 770 | 681 | 974 | 1525 | 100-550 |
| 24.00 h | 570 | 600 | 770 | 1311 | < 150 |
| ACTH (ng/1) | < 10 | < 15 | - | < 10 | < 10-80 |
| 11-Deoxycortisol | |||||
| Basal | 182 | 71 | 161 | 177 | 28-84 |
| With metyrapone3) | 710 | - | - | - | |
| DOC (pmol/l) | - | - | - | 2010 | 85-610 |
| Aldosterone (pmol/l) | - | - | - | 1550 | 30-130 |
| Testosterone (nmol/l)4) | 17 | 16 | 2.6 | 2.3 | 1.0-3.2 |
| Oestradiol (pmol/l) | 1335 | 232 | 67 | 156 | 21-59 |
| Luteinizing hormone (µg/l) | |||||
| Basal | <1 | 1.1 | - | 1.8 | > 15 |
| Peak after GnRH3) | <1 | - | - | 2.1 | > 35 |
| b) Other | |||||
| Potassium (mmol/l) | 4.2 | 4.0 | 1.9 | 2.9 | 3.5-5.5 |
| Glucose (mmol/l): | |||||
| Fasting | 4.2 | 4.7 | 7.1 | - | 3.5-5.5 |
| After glucose orally5) | 9.6 | - | 15.2 | 16.26) | |
rise in serum cortisol or testosterone. Plasma potassium was normal, and a 50 g oral glucose tolerance test showed only mild diabetes mellitus. Urinary free cortisol, which was greatly increased, failed to suppress with dexamethasone; urinary 17-OGS were three times the upper limit of normal, and again there was no suppression with dexamethasone; however, there was a 50 % increase in urinary 17-OGS with metyrapone, and together with the rise in serum 11- deoxycortisol mentioned above, this suggested that metyrapone might be ef- fective in blocking cortisol synthesis. Basal urinary DOC was greatly increased, while urinary aldosterone was subnormal.
| Patients | Normal range2) | ||||
|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | ||
| Urine - 24 h | |||||
| Free cortisol (nmol) | |||||
| Basal | 1540 | 866 | 12 500 | 18 280 | < 270 |
| Dexamethasone3) | 1160 | - | - | - | - |
| 17-OS (umol) | 132 | 279 | 137 | 108 | < 50 |
| 17-OGS («mol) | |||||
| Basal | 152 | 240 | 268 | 303 | < 50 |
| Dexamethasone3) | 184 | - | - | - | - |
| Metyrapone | 224 | - | - | - | - |
| Pregnanetriol («mol) | - | 7.2 | 6.3 | 21 | < 6 |
| Free DOC (pmol) | 2187 | 2354 | 1410 | 1325 | 45-242 |
| Aldosterone (nmol) | 1.4 | 464 | 40 | 13 | 14-55 |
| Blood pressure | 140/100 | 210/130 | 170/90 | 180/100 | |
1) Results quoted here are those when first assessed at Hammersmith Hospital; blood samples at 09.00 h unless otherwise stated.
2) Normal ranges are for post-menopausal women.
3) See text for full details.
4) Normal male range is 10-28 nmol/l.
5) Blood sample taken 120 min after glucose 50 g orally.
6) Random sample at another hospital just before insulin commenced.
These preliminary investigations suggested an adrenal tumour, so the pa- tient was readmitted in May 1975 for localisation studies and with a view to adrenalectomy. She had deteriorated rapidly over the intervening 2 months with the development of proximal muscle weakness, hypokalaemia (3.2 mmol/l), hypertension (BP 210/120) and a steroid psychosis.
Localisation studies
A plain radiograph of the abdomen was normal. Arteriography and veno- graphy both showed a right adrenal tumour, confirmed by adrenal scanning
with [13]]] 19-iodocholesterol with the best delineation at 7 days. Venous sam- pling of serum cortisol levels correctly localised the tumour, but simultaneous estimations of serum testosterone were unhelpful.
Operation June 1975
Most (428 g) of a large right adrenal tumour was removed by one of us (RBW). Complete excision was not possible and the tumour had already in- vaded the local veins. The left adrenal was free from tumour.
Post-operative progress (Figs. 1 and 2)
There was initially good progress with a rapid return to normal of the mental
ADRENALECTOMY
DIED
10,000
5,000
Serum steroid levels (nmol/l or pmol/l )
OESTRADIOL CORTISOL
1,000
500
11-DEOXYCORTISOL
100
50
TESTOSTERONE 17- HYDROXYPROG
10
1975
1976
Cortisol nmol/l
11-deoxycortisol nmol/l
☐
☐ Testosterone nmol/l
Oestradiol pmol/l
☐
☒
☐ 17-alpha-hydroxyprogesterone nmol/l (normal < 18) op’DDD
☒ Metyrapone
ADRENALECTOMY
DIED
10,000
DOC
5,000
24hrs Urine excretion of steroids (jumol, nmol, or pmol )
PREGNANETRIOL CORTISOL
1,000
500
17-OGS
17-OS
100
50
ALDOSTERONE
10
1975
1976
· Free cortisol nmol
Free DOC pmol
0-o Aldosterone nmol
Pregnanetriol nmol
V -V 17-OGS umol
4-4 17-OS umol
op’DDD
☒ Metyrapone
state and the blood pressure and plasma potassium, and the disappearance of the physical signs of Cushing’s syndrome. Serum cortisol became normal at 09.00 h (257 nmol/l) and increased to 698 nmol/l with insulin-induced hypo- glycaemia, showing a normal response. Serum 11-deoxycortisol and urinary free cortisol, 17-OGS, 17-OS and DOC also became normal. The patient remained well for nearly a year until April 1976, when there was a recurrence of facial plethora, accompanied by significant increases in the concentrations of all the serum and urinary steroids that had initially been high. Treatment with op’DDD (“Mitotane”, Calbio Pharmaceuticals) was commenced, and the dose was increased to 8 g/day. There was neither clinical nor biochemical improve-
ment, and on the 10th day therapy was stopped owing to severe systemic symp- toms and an extensive rash. In July 1976 metyrapone (“Metopirone” CIBA Laboratories) was started, increasing the dose to 1.5 g/day. There was no ob- jective improvement, and serum and urinary steroid values continued to in- crease. There was progressive deterioration with worsening of the physical signs, a cerebrovascular accident and severe depression. The patient died in December 1976.
Patient 2
This lady had been hypertensive since the age of 43, and her periods ceased at age 45 years. In August 1975, aged 47 years, Cushing’s syndrome was diag- nosed with symptoms of weight gain and hirsutism of 4 months duration. The diagnosis was confirmed biochemically and an excretion urogram indicated a left adrenal mass. At operation 400 g of an adrenal carcinoma were removed (Mr. J. S. Mously) but complete ablation was impossible. There was no change in symptoms, and the patient was referred to us for further treatment. On examination, the striking features were hirsutism, powerful muscles and hyper- tension (BP 210/130). There was slight facial plethora but there were no bruises, and no striae, and skin thickness was normal.
Biochemistry (Table 1)
There were increased serum concentrations of cortisol with undetectable plasma ACTH. Serum testosterone was within the normal male range; serum oestradiol was also increased, but not markedly so. There was no increase in serum testosterone or cortisol after “Synacthen Depot”. Plasma potassium and fasting blood glucose were normal. The urinary free cortisol was greatly ele- vated, but not so much as in the other 3 patients. Urinary 17-OS, 17-OGS, pregnanetriol and free DOC were all clearly increased.
Skull and chest radiographs were normal, but a second excretion urogram demonstrated a left adrenal mass.
Progress
The risks of a second operation on the primary tumour exceeded the prob- able benefits, so treatment with op’DDD was commenced, gradually increasing to 8 g/day. The drug had to be stopped on two occasions because of diarrhoea, nausea and vomiting. At the end of one month, there was biochemical improve- ment, with progressive reduction in serum cortisol and most of the urinary steroids (Figs. 3 and 4). However, most of these soon started to rise again, and there was no response to 2 further courses of op’DDD. Although the blood pressure fell, there was no response to op’DDD in any other clinical aspect.
10,000
5,000
Serum steroid levels (nmol/l or pmol/l )
CORTISOL
1,000
500
11-DEOXYCORTISOL
100
OESTRADIOL
50
ba TESTOSTERONE
DIED
10
1976
Cortisol nmol/l
^ 11-deoxycortisol nmol/l
☐
☐ Testosterone nmol/l
Oestradiol pmol/I op’DDD
Z ☒
The patient deteriorated and progressively developed enlarged hard cervical lymph nodes and hepatomegaly, suggesting carcinomatosis. Metastases, first shown on the chest radiograph in May 1976, continued to increase in size. The patient died in January 1977.
Patient 3
This 58 year old lady had had typical symptoms of Cushing’s syndrome for 4 months in July 1975 when the physical signs and biochemical tests confirmed the diagnosis. A plain radiograph of the abdomen showed downward displace- ment of the left kidney and calcification above it. In July 1975 as much as possible of an adrenal carcinoma was removed (Mr. J. S. Mously). The spe- cimen weighed 308 g and had areas of haemorrhage and necrosis. There was clinical and biochemical remission for 3 months after which the patient started
10,000
DOC
5,000
24hrs Urine excretion of steroids ( jumol , nmol, or pmol )
CORTISOL
1,000
500
17-OGS
17-OS
100
50
ALDOSTERONE
DIED
10
TI
1976
· Free cortisol nmol
Free DOC pmol
o Aldosterone nmol
Pregnanetriol nmol
17-OGS umol
A 17-OS umol
☒ op’DDD
to relapse. In November 1975 she was referred to us for further management. On examination, typical features of Cushing’s syndrome were found, but hir- sutism was only slight, the blood pressure was 170/90.
Biochemistry (Table 1)
Serum cortisol and 11-deoxycortisol were increased, but testosterone and oestradiol were normal. HCG failed to produce increases in serum cortisol, testosterone or oestradiol. Plasma potassium was low and the 50 g oral glucose tolerance test showed diabetes mellitus. Urinary free cortisol, 17-OS, 17-OGS and free DOC were all increased, but urinary aldosterone was normal.
Progress
op’DDD was commenced in November 1975, was increased to 8 g/day, and was well tolerated. Within 2 weeks, the clinical signs of Cushing’s syndrome started to regress and the plasma potassium became normal, but the blood pres- sure remained unchanged. In January 1976 the patient was reassessed while taking 8 g/day of op’DDD. There were obvious improvements in facial plethora, obesity (weight reduction of 4 kg) and conjunctival oedema. There were pro- gressive decreases in urinary free cortisol, 17-OGS, 17-OS and pregnanetriol (Fig. 5). There was no significant change in urinary DOC but aldosterone ex- cretion was diminished. Serum cortisol fell from 974 to 756 nmol/l, and 11-
10,000
DIED
5,000
24hrs Urine excretion of steroids (jumol, nmol, pmol )
CORTISOL DOC
1,000
500
PREGNANETRIOL
100
17 - OGS
50
17-OS
10
ALDOSTERONE
Nov Dec Jan 1975 1976
· Free cortisol nmol
Free DOC pmol
o Aldosterone nmol
☒
☒ Pregnanetriol nmol
17-OGS umol
A
17-OS umol
☒ op’DDD
deoxycortisol from 161 to 107 nmol/l, while there were no significant changes in serum testosterone or oestradiol. The final deterioration was swift, and the patient died in January 1976.
Post-mortem examination
This showed a left adrenal tumour 14 x 11 x 5 cm, with peritoneal meta- stases. The liver, lungs, bone, brain and right adrenal gland were all free from tumour. The pituitary gland was normal except for hyaline changes in cortico- trophin-producing cells (Crooke’s cells).
Patient 4
This 68 year old lady was admitted to hospital in February 1978 complaining of weakness and back pain. She had been treated for mild hypertension for the previous 5 years. Her health had deteriorated from November 1977, when she became agitated and depressed. The diagnosis of Cushing’s syndrome was suggested in February 1978 by central obesity, muscle weakness, hypokalaemia (potassium 1.3 mmol/l), hyperglycemia (glucose 16.2 mmol/l) and hypertension (BP 180/100). The physical signs of Cushing’s syndrome were minimal, and hirsutism, facial plethora and “mooning”, striae, easy bruising and conjunc- tival oedema were all absent initially.
Biochemistry (Table 1)
Serum cortisol was the highest of the 4 patients, and plasma ACTH was un- detectable. Serum testosterone was normal but serum oestradiol was slightly increased; serum LH was low, and there was no significant increase after GnRH. Plasma potassium remained subnormal. Urinary free cortisol was ex- tremely high, and urinary 17-OS, 17-OGS and pregnanetriol were increased. Urine free DOC was increased, but urinary aldosterone was not.
Radiographs of the pituitary fossa and chest were normal, but the lumbar spine showed severe osteoporosis, as indicated by vertebral collapse.
Localisation studies
Plain radiographs of the abdomen and an excretion urogram were normal. The site of the adrenal tumour on the right side was correctly located by ultra- sound (which also showed an abnormal mass in the liver). An arteriogram sugggested that the circulation to the right adrenal gland was abnormal, but the appearances were not definite. Hence venous sampling was attempted but this failed to localise the tumour since the right adrenal vein could not be entered, and samples from other sites were uniformly high. An isotopic liver scan showed an abnormal mass.
Progress
Metyrapone was commenced in March 1978 and was increased to 2.5 g/day. The effects were observed for 2 weeks; there was no clinical benefit and blood pressure remained elevated. There was no consistent reduction in serum or uri- nary cortisol values, and serum 11-deoxycortisol concentrations did not change. However, there was a 10-fold rise in urinary DOC excretion, without a change in urinary aldosterone; serum DOC increased 4-fold but serum aldosterone did not change. The condition of the patient deteriorated with drowsiness and severe back pain.
Operation March 1978
The abdomen was opened anteriorly (RBW). The liver contained a large mass of tumour in the right lobe, which concealed the right adrenal tumour, and there were many small hepatic metastases. No palliative procedure was possible and the patient died 3 days later.
Post-mortem examination
There was a right adrenal carcinoma weighing 20 g, and a tumour-free left adrenal of 3 g. The massive hepatic secondary tumour (15 x 10 x 10 cm) was at the site shown by ultrasonic and isotopic scans. The multiple hepatic meta- stases were each less than 1 cm in diameter. The lungs, bone and brain were free from metastases, and the pituitary gland was normal except for Crookes’ changes.
DISCUSSION
These patients illustrate several interesting features concerning the nature and treatment of functioning adrenal cortical carcinomas. The diagnosis was sug- gested initially in all by the short history of the signs of Cushing’s syndrome (mean of 6 months) and in patient 2 by significant virilisation. The physical signs were least apparent in patient 4, despite the fact that she had the highest cortisol values, suggesting that there was insufficient time for all the signs to develop.
The biochemical features of adrenal carcinoma were the very high amounts of cortisol excretion in 3 patients when first seen by us (and in the 4th patient later), since values exceeding 1500 nmol/24 h are exceptional in the commoner pituitary-dependent disease (Burke & Beardwell 1973). Moreover, greatly ele- vated values of serum oestradiol, testosterone and 11-deoxycortisol are not usual in the benign types of Cushing’s syndrome (Liddle 1974). Urinary DOC and aldosterone are usually close to normal in pituitary-dependent Cushing’s syn-
drome (Cope & Loizou 1976) whereas all our patients with adrenal carcinomas had very high values for urinary DOC, and patient 2 also had substantially increased urinary aldosterone. The elevations in urinary DOC without corres- ponding increases in urinary aldosterone, and the increase in serum 11-deoxy- cortisol suggest that relative insufficiency of 11-hydroxylation of steroids may be a feature of these adrenal carcinomas, as noted by Lipsett & Wilson (1962) and by our own group (Dennis et al. 1967). If 11-hydroxylation is a rate-limiting step, then therapeutic efficacy of metyrapone might be anticipated. This meta- bolic block was not total since metyrapone caused further increases in urinary and plasma DOC values. However, urinary and plasma aldosterone values remained unchanged, and metyrapone neither reduced blood pressure nor al- leviated the physical signs of Cushing’s syndrome.
Correlation between the biochemical and clinical features was interesting. Only patient 2 suffered from severe virilisation, and this was probably due to the very high level of serum testosterone unopposed by a very high serum con- centration of oestradiol; in contrast patient 1 (without virilisation but with equally high serum testosterone levels) was perhaps protected by the very high concentration of oestradiol.
Suppression of pituitary gonadotrophins in these post-menopausal females was possibly due to increased serum concentrations of sex steroids.
At our first assessment, only patient 2 had severe hypertension and this may have been due to her very high output of aldosterone. Patients 1, 3 and 4 all had milder hypertension, responding (in patient 1) to removal of most of the tumour. The relative roles of DOC and cortisol in the genesis of hypertension could not be distinguished. since treatment affected these steroids similarly.
Severe hypokalaemia was found in patients 3 and 4 who had the highest cortisol values; it is interesting that patient 2 who had the highest urinary excretion of DOC and aldosterone did not have such severe hypokalaemia. We interpret these results by considering that despite the relatively weak mineralo- corticoid action of cortisol, it can cause hypokalaemia if present in enormous concentrations.
Functioning adrenal carcinomas are usually autonomous (Welbourn & Sell- wood 1969; Liddle 1974), and we confirm this since dexamethasone, HCG and “Synacthen Depot” produced no significant changes in steroid levels.
Localisation studies correctly predicted the sites of tumours in all patients. In patient 3 a plain radiograph of the abdomen, and in patient 2 an excretion urogram were adequate for diagnosis. Ultrasound was the most useful method in patient 4 since it correctly identified both the tumour, and the large hepatic metastasis. Arteriography and venography both gave one definite and one in- conclusive result, and we prefer the non-invasive methods.
Immediate treatment by removal of as much cancer tissue as possible is worthwhile. In patients 1 and 3 this resulted in several months of complete
clinical and hormonal remission, but patient 2 showed no improvement even though, like others, she showed no evidence of metastases at the time of opera- tion. Palliation was impossible in patient 4 since she presented in a terminal state.
In the largest series of patients with adrenal carcinoma, op’DDD therapy was said to have caused clinical improvement in a third, regression of malig- nant tissue in a third, and reduction of high steroid levels in about two thirds (Hutter & Kayhoe 1966b). If a further operation to remove tumour is not fea- sible, then op’DDD is worth a trial; patient 3 in our series obtained an im- pressive clinical and biochemical remission for 2 months, but patients 1 and 2 could only tolerate limited courses of therapy.
Biochemical monitoring of disease activity in our patients showed that steroid levels tended to change in parallel, the hormonal pattern remaining relatively constant. Therefore, to check for disease reactivation, we recommend that se- quential measurements are made of several steroids including those which showed the most severe initial abnormalities. We did not observe the change reported by Temple et al. (1969) that, in Cushing’s disease, op’DDD could be used to reduce selectively the serum cortisol levels, without a concomitant re- duction in aldosterone.
In our group, the mean duration of survival after the onset of symptoms was 17 months, and that after operation was 10 months. Short survival after diag- nosis is typical of adrenal carcinoma and agrees with our experience of 8 other patients (amalgamating the results of Welbourn & Sellwood 1969; Welbourn et al. 1971). MacFarlane (1958) reported the mean survival after diagnosis of 9 untreated patients as 4 months. However, with operations and op’DDD some patients have survived much longer (Hajjar et al. 1975; Becker & Schumacker 1975; Ostuni & Roginsky 1975).
In conclusion, functioning adrenal cortical carcinoma remains a lethal con- dition despite advances in chemotherapy. Biochemical screening to measure multiple steroids as described in this paper is helpful both for diagnosis, and for monitoring the response to therapy. Immediate surgical ablation of the tumour offers the best chance of palliation, and if an operation is impossible then op’DDD should be used.
ACKNOWLEDGMENTS
We thank Dr. D. A. F. McGill, Dr. M. P. Mahoney, Mr. J. S. Mousley and Dr. J. H. Baron for referring their patients. We thank Dr. P. D. Lewis (Histopathology), Dr. J. M. Kjeld (testosterone and oestradiol assays), Dr. K. Fotherby (urinary 17-OS, 17- OGS and pregnanetriol estimations), Dr. Lesley Rees (ACTH assays), Dr. G. Groom (plasma 17-hydroxyprogesterone assays) and the staff of the Radioimmunoassay La- boratories (all other hormone assays). The results of the catheter studies were kindly
provided by Dr. D. Allison and adrenal scan by Dr. P. Lavender. We also thank the nurses on our Metabolic Unit.
G. F. Joplin acknowledges generous help from the Cancer Research Campaign, CIBA- GEIGY, Ltd., and Dr. E. Vogl of Hoechst Ltd. for supplies of GnRH.
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Received on January 26th, 1979.