CUSHING’S SYNDROME: ADRENOCORTICAL HYPERACTIVITY SECONDARY TO NEOPLASMS ARISING OUTSIDE THE PITUITARY-ADRENAL SYSTEM1
BY M. FRIEDMAN, P. MARSHALL-JONES, AND E. J. ROSS
(From the Medical Unit and Metabolic Ward, University College Hospital and Medical School, London, W.C.1)
IN 1928, Brown reported the case of a 45-year old woman who developed the clinical picture of Cushing’s syndrome. Deterioration was rapid and she died within five months of the onset of her illness. At post mortem she was found to have oat-cell carcinoma of the lung and bilateral adrenal hyperplasia. Brown did not comment on the presence of the carcinoma, which he appears to have ac- cepted as an incidental finding. Since that time it has become increasingly recognized that Cushing’s syndrome may be associated with malignant neo- plasms of various organs which normally do not participate in the regulation of the pituitary or adrenal glands. The neoplasms most frequently associated with Cushing’s syndrome have been bronchus, thymus, and pancreas (Allott and Skelton, 1960; Riggs and Sprague, 1961); bronchogenic carcinoma of the anaplastic or oat-cell type is the most frequent.
The clinical presentation of these patients is extremely variable. The com- monest mode of presentation of the disease is characterized by progressive weakness, severe hypokalaemic alkalosis, and muscle wasting and is associated with a pattern of electrolyte loss suggestive of excessive mineralocorticoid activity which is extremely rare in non-malignant Cushing’s syndrome (Ross, Marshall-Jones, and Friedman, 1966). Some present with oedema. The clinical picture does not usually suggest adrenal hyperactivity, but the biochemical findings in the urine and plasma and the post-mortem findings are typical of severe adrenocortical overactivity. A few patients, however, develop a rapid onset of the typical clinical features of Cushing’s syndrome with the charac- teristic obesity, moon facies, purple striae, hypertension, and diabetes. Both the electrolyte changes and the usual clinical features of Cushing’s syndrome may occasionally be completely absent (Friedman, Mikhail, and Bhoola, 1965). In our experience the prognosis when adrenocortical overactivity occurs in association with a neoplasm is extremely poor; death often supervenes within days of the presentation of the first symptom or sign suggesting the develop- ment of this metabolic complication of the carcinoma. One of the major diffi- culties in carrying out an intensive series of investigations on this group of
1 Received July 18, 1965.
patients has been their relatively short survival after the initial diagnosis was made.
Over the past three years we have observed nine patients with adrenocortical hyperplasia secondary to extra-adrenal neoplasms (Table I). Eight have had bronchogenic carcinoma, while one patient had a parathyroid carcinoma. We believe that this is the first time this complication has been reported in associa- tion with a parathyroid carcinoma. The purpose of this paper is to report on the clinical findings and the biochemical investigations carried out on these patients and contrast them with the findings on the fifty cases with Cushing’s syndrome described in the preceding paper (Ross, Marshall-Jones, and Friedman, 1966). We also wish to report the effect of the administration of corticotrophin and dexamethasone on these patients. All comparisons with non-neoplastic Cushing’s syndrome refer to the series described in the above paper unless otherwise stated. The term ‘Cushing’s syndrome’ and ‘adrenocortical hyper- plasia’ (i.e. hyperactivity) are used synonymously in this paper.
Methods
Plasma sodium, potassium, chloride, bicarbonate, and urea and glucose con- centrations were determined on the Technicon Autoanalyzer (Dr. F. V. Flynn). Haematological investigations were done in the hospital routine laboratory (Professor M. Maizels). Plasma 11-hydroxycorticoids (‘plasma cortisol’), urinary 17-ketogenic, and 17-ketosteroids were measured as described by Ross, Marshall- Jones, and Friedman (1966). Details of the procedure used for the corticotrophin stimulation test and dexamethasone suppression test are also given in this previous paper. Cortisol in urine was determined on 24-hour specimens of urine hydrolysed with HCI at pH 1 for 48 hours at room temperature, extracted with chloroform and taken to dryness. The residue was chromatographed on a florisil column, eluted with 25 per cent. methanol in chloroform and taken to dryness. This residue was chromatographed on paper in the system of Zaffaroni, Burton, and Keutmann (1950) using 25 per cent. propylene glycol in methanol for 48 hours. The band corresponding to the cortisol marker was eluted and rechromatographed in the ‘C’ system of Bush (1952). The band corresponding to the cortisol marker was eluted with methanol, taken to dryness and determined by a modified blue tetrazolium reaction (Chen, Wheeler, and Tewell, 1953). In each case colours were read against a paper blank from the same chromatogram. Corticosterone in urine was determined by the same pro- cedure excepting that the first paper system was run for only 16 hours and corticosterone markers were employed.
Case Studies
H. B., a 55-year old man, was admitted to U.C.H. in January 1963 under the care of Professor C. E. Dent. He gave a six months history of increasing breathlessness and weight loss. Three months before admission he noticed that both his upper and lower limbs were becoming increasingly weak. By the end of November 1962 he was unable to walk due to weakness, and took to his bed.
| weight | deposits | Adrenal | glands | of | diag- | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Aos Patient Sex | Blood pressure | Obesity or gain | Strias | Hirntim | Thirst and polyuria | Florid faos | Muscle weakness | Diabetes Pigmentation | Primary carcinoma | Secondary | Histology of carcinoma | Wright in g. | Metastases Hyperplasia | Arst symptoms Survival after carcinoma | Survival after nosis of adrenal hyperactivity | brain at autopsy Pituitary and | Other findings | ||
| H. B. 55 M | 140/7 | 1 | 1 | 4 | + | 1 | X | + + Bronchus | Liver, pleura, hilar glande | Oat cell | 80-6 | + | + | 6 months | 18 days | Normal | .. | ||
| M. B. 48 F | 125/75 | - | + | Para- thyrold | Bones | Parathyroid carcinoma | 35 | + - | 2 days | Normal | |||||||||
| M. O. 57 M | |||||||||||||||||||
| 190/100 | + | - .. | Bronchos | Hilar glands, pericardtum, liver | Oat cell carcinoma | Enlarged | + | + | ? 8 months | 10 days | Normal | Ankle oedema | |||||||
| D. M. 37 M | 160/100 | - - | Bronchus | ? | Oat cell carcinoma diagnosed on blopay | ? | ? | ? | 40 days | ? | Marked oedema. Autopsy refused | ||||||||
| W. B. 68 M | 104/80 | - | + + | - | Bronchus | Mediastinal glande | Oat cell carcinoma | ? | ? | ? | 6 months | 2 days | ? | Superior vena- caval obstruc- | |||||
| W. H. 48 M | 135/85 | - | + | Bronchu. | Liver, bone | Oat cell carcinoma | Enlarged | + - | 3 months | 14 days | Normal | tion. Autopsy refused Ankle swelling | |||||||
| R. N. 56 F | 170/95 | + | + | + | + | + + | Bronchus | LAver | Oat cell carcinoma | 32 | + - | 2+ months | 6 weeks | Normal | Superior venacaval | ||||
| obstruction | |||||||||||||||||||
| R. C. 56 M | 200/105 | - | + | - | Bronchos | Liver, bone | Oat cell carcinoma | ? | ? | ? | 5 months | 9 days | ? | Gross ankle oedema and | |||||
| demonstrated by sputum cytology | ascitis. Autopsy refused | ||||||||||||||||||
| 8. M. 59 M | 170/100 | + | + | + | + | - | Bronchus | Lymph glands | ? | ? | ? | ? | 2 years | 19 weeks | ? | Superior venacaval obstruction. No autopay obtained | |||
ADRENOCORTICAL HYPERACTIVITY IN CARCINOMA
He denied any polydipsia, but stated that for the past two months he was waking up at least three times a night to pass urine. His wife stated that over the course of the preceding three months his skin colour had become increasingly dark, in spite of the fact that he was not exposed to the sun. He denied taking purgatives or diuretics. His bowels were regular and he passed one stool a day of normal appearance and consistency. He had smoked 20 cigarettes a day for the past 20 years. There was nothing significant in his past history.
| Urinemg.|24 hrs. | glu- ml. | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| urea ml. | Na | K | Cl | HCO, | ml. | ketosteroids | Plasma pg./100 | cortisol ml. | plasma | blood mg.|100 | ||
| Patient | Plasma mg./100 | Plasma | g./100 | ketogenio steroids | a.m. | m.n. | proteins | Fasting | ||||
| Plasma mEq./I. | mEq./I. | Plasma mEq./l. | Plasma mEq./l. | Hb. | 17 | 17 | 9 | 9 | Total | 0036 | ||
| H. B. | 32 | 138 | 2.2 | 91 | 36 | 12.1 | 67 | 156 | 79 | 69 | 5.5 | 130 |
| 78 | 146 | 76 | 60 | |||||||||
| 25 | 114 | 63 | ||||||||||
| 77 | 56 | |||||||||||
| M. B. | 69 | 135 | 1.7 | 87 | 27.3 | 8.2 | 56.2 | 5.5 | ||||
| M. C. | 42 | 137 | 1.7 | 83 | 38 | 11.1 | 27.6 | 69 | 56-7 | 56.4 | 5-8 | .. |
| 86-8 | 80-8 | |||||||||||
| D. M. | 33 | 137 | 3-6 | 101 | 27.4 | 12.5 | 13 | 67 | 72.2 | 5-4 | 80 | |
| W.B. | 18 | 144 | 1.8 | 77 | 53 | 13.0 | 47 | 221 | 44-8 | .. | ||
| mg./litre | ||||||||||||
| W. H. | 59 | 142 | 1.9 | 77 | 42.5 | 15.2 | 3.9 | 85 | ||||
| R. N. | 28 | 142 | 3.2 | 98 | 33-0 | 15-4 | 32 | 84 | 64.0 | 38-4 | 6.4 | 190 |
| 34 | 74 | 59.0 | 114 | |||||||||
| 45 | 127 | 93 | 238 | |||||||||
| 87 | 59 | 214 | ||||||||||
| R. C. | 44 | 154 | 2.9 | 100 | 89.5 | 10.0 | 111 | 337 | 46-3 | 43.3 | 5.0 | 85 |
| mg./litre | 57-6 | 64.8 | ||||||||||
| S. M. | 24 | 142 | 2.9 | 95 | 31 | 15-6 | 32 | 46 | 37-4 | 37-2 | .. | 155 |
| 51 | 69 | 30-0 | 33-2 | |||||||||
On examination he looked ill and was wasted. His skin was dry and lax with evidence of recent weight loss. Marked generalized brownish pigmentation of the skin was present, which was accentuated round both nipples. He had patchy pigmentation of the mucous membranes of his mouth. No bony tender- ness or deformity. The liver edge was palpable 1 cm. below the costal margin. This was smooth and not tender. He had marked symmetrical weakness of all four limbs, involving both proximal and distal groups of muscles. The trunk muscles were very weak and he was unable to support the weight of his head. No reflexes were elicited. Plantar responses were flexor. No abnormality was found of the cranial nerves or the sensory nervous system. A number of bruises were present over the body, precipitated by minor trauma. The facies did not resemble in any way that seen in Cushing’s syndrome (see Table I).)
Investigations
Plasma electrolyte and urea concentrations and haemoglobin estimation are shown in Table II. The urinary excretion of potassium was 134 mEq./24 hours when the plasma potassium concentration was 2.2 mEq./L. Urinary sodium excretion was 102 mEq./24 hours. White blood cells were 8,000/cu.mm., and
erythrocyte sedimentation rate (E.S.R.) was 77 mm./hr. Amino-acid chromato- gram of the urine was normal. Total plasma protein concentration was 5-5 g./ 100 ml. The electrophoretic strip showed a reduction in the plasma albumin. The fasting blood glucose concentration was 130 mg./100 ml., which rose to 350 mg./100 ml. after 50 g. of glucose and fell to 290 mg./100 ml. at 120 minutes. The sputum yielded a heavy growth of Strep. pneumoniae. No acid-fast bacilli
TABLE III Results of Corticotrophin (ACTH) Stimulation and Dexamethasone Suppression Tests
| Control day | ACTH | Day 1 | ACTH | Day 2 | Deramethasons 10 mg. daily for 2 days | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient | 17-ketosteroids mg.|24-hrs. | 17-ketogenic steroids mg.|24-hrs. | Plasma cortisol pg./100 ml. | 17-ketosteroids hrs. | hrs. 17-ketogenic steroids | Plasma cortisol AOTH ug.|100 ml. 5 hrs. | hrs. =17-ketosteroids | 17-ketogenic steroids mg./24-hrs. | Plasma cortisol ACTH ml. 5 hrs. | 17-ketosteroids hrs. | 17-ketogenic steroids mg./24-hrs. | Plasma cortisol ml. |
| mg./24 | mg.|24 | after | img.|24 | after pg.|100 | mg./24 | μg./100 | ||||||
| H. B. | 25 | 156 | 79 | 88 | No = | 56-8 | 99 | 60-8 | 37 | & | ₹ | |
| 146 | ||||||||||||
| M. C. | 27-6 | 69 | 56-7 | .. | 90.0 | |||||||
| 88.8 | 33 | 63 | 102 | |||||||||
| 12 mg. for 2 days | ||||||||||||
| D. M. | 13 | 67 | 72.2 | 13 | 36 | |||||||
| R. N. | 32 | 84 | 59.0 | 56 | 36 | 90.0 | 59 | 45 | 64.0 | 43 | 103 | 67-4 |
| 34 | 74 | |||||||||||
| 8 mg. for 1 day 16 mg. for 1 day | ||||||||||||
or malignant cells were detected in his sputum on numerous examinations. An X-ray of his chest revealed a diffuse opacity in the right lower lobe which was thought to be inflammatory and which partially cleared with antibiotics. Bronchoscopy (Dr. H. Nicholson) revealed no evidence of a neoplasm of the bronchus. X-ray of his skeleton was normal. The electrocardigram (E.C.G.) showed evidence of hypokalaemia.
The results of the estimations of plasma and urine steroids are shown in Table II. The response to corticotrophin stimulation and dexamethasone sup- pression are shown in Table III and Fig. 1.
Treatment and management
This patient’s main presenting symptoms and major disability were due to his extreme muscular weakness which was a result of his hypokalaemia. In spite of giving him 156 mEq. of potassium daily his plasma potassium remained below 3.0 mEq./1. During the same period he excreted between 60 and 130 mEq. of potassium daily in his urine, indicating a failure of renal tubular con- servation of potassium. The tests of adrenal function clearly indicated that this patient had adrenocortical overactivity. However, the usual clinical signs of Cushing’s syndrome were absent. The recent onset of generalized pigmenta- tion, the severe persistent hypokalaemic alkalosis, and the elevated E.S.R. were all in favour of the adrenal overactivity being due to an extra-adrenal carci- noma. In spite of our various investigations directed mainly towards finding a carcinoma of the bronchus, we were unsuccessful. His condition deteriorated rapidly due primarily to weakness of his respiratory muscles which led to diffi- culty in breathing and coughing. In view of the uniformly poor prognosis of Cushing’s syndrome associated with extra-adrenal carcinoma, we decided to
remove both his adrenals in the hope of obtaining a temporary remission of the disease, the ultimate prognosis depending on the primary tumour which we hoped was still small and localized and, therefore, still operable. Accordingly, Mr. B. J. Harries removed both adrenals, which were markedly enlarged (the left gland weighed 14.5 g. and the right gland 16.1 g.). Histology of the adrenals showed hyperplasia of the cortex with small islands of poorly differentiated
Dexamethasone
16
Died
mg./d.
8
20
KCI
g/d. 10
ACTH
80i.u./d.
Adrenalectomy
Plasma K m.Eq/1.
4
3
:
17 KGS
140
mg./24hr
120
100
80
60
Plasma
40
Cortisol pg./100ml.
20
9 a.m. midnight
Herbert B.
18
25
b. 1908
Jan
1963
extra-adrenal carcinoma cells scattered throughout both adrenal glands. The quantity of neoplastic cells were thought to be insufficient to account for more than a small percentage of the weight increase of the glands. During the first 36 hours following the adrenalectomy he seemed to be making a good recovery, on large doses of hydrocortisone, but then he died suddenly. The immediate cause of his death could not be determined.
At post-mortem (Dr. P. M. Sutton) a small oat-cell carcinoma was found arising at the origin of the apical posterior segment of the bronchus of the left upper lobe, which had infiltrated the lung to a depth of 0.5 cm. There were secondary deposits on the pleural surface of the upper lobe in the oblique fissure, the largest being 1 cm. in diameter. One hilar gland contained secondary carci- noma. Secondaries were present in the liver. Histological examination of the thalamus, hypothalamus, and pituitary was normal.
M. B., a 48-year old woman, was admitted to the Metabolic Ward under the care of Professor C. E. Dent in 1960. She gave a six months history of anorexia,
weight loss, nausea and vomiting, and skeletal pain. Her plasma calcium con- centration was 19.9 mg./100 ml. with a plasma phosphorus concentration of 2.2 mg./100 ml. and an alkaline phosphatase concentration of 36 King-Armstrong units. X-ray showed sub-periosteal erosions of the phalanges of the hands. A diagnosis of primary hyperparathyroidism was made. Mr. D. R. Davies ex- plored her neck and found an invasive parathyroid carcinoma. The tumour was resected and following the operation her plasma calcium concentration fell to 6.4 mg./100 ml. and she developed tetany. Subsequently her plasma calcium returned to normal. In 1961 she had a further episode of hypercalcaemia associated with a recurrence of the carcinoma. A further neck exploration was carried out, during which further malignant parathyroid tissue was removed. Unfortunately the surgeon was not able to remove all the parathyroid tumour. Postoperatively she was given radiotherapy to both the neck and the mediasti- num which produced a fall in plasma calcium to normal levels. In February 1962 she once again became hypercalcaemic with plasma calcium concentration rising to 17 mg./100 ml. We were able to control her plasma calcium by the administration of large doses of disodium hydrogen phosphate given intra- venously. The calcium data of this patient has been published in greater detail elsewhere by Dent (1962), where she is described as Mrs. Margaret B. She was later started on cortisone, 450 mg. daily. On this, her plasma calcium concen- tration was maintained between 11 and 12 mg./100 ml. While in hospital she developed extensive calcified plaques over her trunk and limbs. Some of these became gangrenous and were extremely painful. After five weeks on this large dose of cortisone she refused all therapy, and we were obliged to discontinue the cortisone without gradually tailing off the dose. Forty-eight hours after stopping the steroids her plasma cortisol was measured, the expectation being that her adrenals would be markedly suppressed by the large dose of steroids that she had been given. To our surprise, her plasma cortisol was 56-2 µg./100 ml. At this stage her plasma potassium was 2.2 mEq./1. and her plasma bicarbonate was 27.3 mEq./1. The significance of this was not appreciated at the time. She died two days later. Autopsy revealed secondary deposits of parathyroid tumour in the vertebral column. The combined weight of the adrenals was 35 g. Histology of the glands showed diffuse cortical hyperplasia. The pituitary and the brain were normal.
M. C., a 57-year old toolmaker, divorced from his wife three years previously and living alone, became depressed and withdrawn, and was admitted to St. Pancras Mental Observation Ward (Dr. E. W. Dunkley) with a history of recent mental confusion. He had smoked 30-40 cigarettes daily since the age of 16.
On examination he was confused, wasted, clinically anaemic, and looked much older than his stated years. B.P. 190/100 mm.Hg. The only physical abnor- mality found was in the chest where the right base was dull to percussion, breath sounds were absent, and vocal resonance was decreased. Numerous rhonchi were heard in the chest. Chest X-ray on admission showed & pleural effusion on the right side; partial collapse of the right lower lobe was seen on screening. There was no evidence of a bronchial carcinoma on the chest X-ray, but sputum examination showed the presence of cells characteristic of anaplastic carcinoma (Dr. F. R. Philps), presumably an oat-cell carcinoma of the bronchus. Investigations are shown in Tables II and III.
Subsequent progress
Large doses of potassium chloride restored the potassium concentration to within the normal range. His condition deteriorated rapidly and he died 39
days after admission to hospital. Autopsy showed a primary oat-cell carcinoma in the right lower lobe with involvement of the hilar glands and pericardium. Secondary deposits were present in the liver and in both adrenal glands.
D. M., a caterer, aged 37, was referred to the Medical Out-patient Depart- ment because of swelling of the face and ankles. He had smoked 40 cigarettes daily for 20 years.
On examination no physical abnormalities were found apart from oedema of the face and of the legs up to the knees. The liver was enlarged 1 cm. beneath the costal margin. Protein was absent from the urine. The blood pressure was 160/100 mm.Hg.
Investigations are shown in Tables II and III.
Course in hospital. The liver rapidly increased in size and its surface became irregular. The patient became jaundiced. The plasma potassium concentration, on repeated weekly estimations, never fell below 3.6 mEq./1., nor was the plasma bicarbonate above 27.4 mEq./1. The patient died within 40 days of first being seen in the Out-patient Department. He never became Cushingoid in appearance. Autopsy was refused.
W. B., a salesman, aged 63, was transferred from the Homeopathic Hospital. He had been admitted there in 1962 with swelling of both legs, hepatomegaly and generalized lymphadenopathy. Gland biopsy of the neck was reported as showing undifferentiated cells of uncertain origin. Chest X-ray showed a widened mediastinum. The patient discharged himself after 10 days. Following this he developed generalized weakness of both legs and was unable to stand. His voice became hoarse and he had developed oedema of the face and neck. On account of this superior vena caval obstruction he was referred to the Radiotherapy Department (Dr. E. W. Emery) for treatment.
Examination on admission showed a confused patient with deep cyanosis and oedema of the face and neck. He had a myasthenic facies with bilateral ptosis and difficulty in holding his head up. He was able to perform only the slightest movement of his limbs. The tendon reflexes were all present but were sluggish. The plantar responses were extensor. No sensory loss was noted.
Investigations are shown in Table II.
Course in hospital. The patient died on the day after admission. Autopsy was refused.
W. H., an engineer, aged 48 years, was referred to Dr. P. J. D. Heaf because of increasing breathlessness. He had smoked 20-30 cigarettes daily for 30 years and had had a ‘smoker’s cough’ with mucoid sputum for four years. Two weeks previously he had noticed streaks of blood in his sputum. He was ad- mitted for bronchoscopy in August 1963.
Examination on admission. Widespread rhonchi were heard over both lung fields, but there were no other abnormal physical signs in the chest. The blood pressure was 135/85 mm.Hg and no oedema was present.
Investigations are shown in Table II. Examination of the sputum revealed cells characteristic of anaplastic carcinoma on one occasion. Chest X-ray showed a large opacity in the left lower zone. Findings on bronchoscopy were narrowing of the left lower lobe bronchus and left main bronchus. Report on biopsy of bronchial mucosa : squamous metaplasia without evidence of carcinoma.
Course. Radiotherapy was given to the left lower lung field and the patient discharged. In November 1963 the patient began to complain of severe pain in the lumbar spine. X-ray examination failed to show evidence of metastases.
He then noticed that his ankles were beginning to swell. He was readmitted. He was found to have oedema up to the knees and a palpable liver 5 cm. beneath the costal margin. The surface of the liver was smooth. His blood pressure was 135/90 mm.Hg. Sugar was absent from the urine.
The patient deteriorated very rapidly following admission and died within a week. Total survival since first observation of ankle swelling, 14 days.
R. N., a housewife, aged 56, was admitted complaining of a non-productive cough and tiredness of four weeks duration. Two weeks prior to admission she had noticed that her neck and face had become swollen, and she developed breathlessness. Her voice had recently become husky. She had smoked 20 cigarettes a day for 20 years.
On examination the skin showed generalized pigmentation, but buccal pig- mentation was absent. The left side of the face and neck was oedematous. The neck veins on the left side were dilated and non-pulsatile. The right internal jugular pulse was pulsatile and elevated 5 cm. above the sternal angle. Slight sacral oedema was present, but no ankle oedema. The blood pressure was raised to 170/95 mm.Hg. The apex of the left lung was dull to percussion and bronchial breathing was heard over this area. The liver was palpable 2 cm. below the costal margin. The left vocal cord was paralysed. Slight generalized muscular weakness was present.
Investigations on admission. Haemoglobin was 15-4 g./100 ml., and white cell count, 15,300 cu. mm. with 85 per cent. polymorphs. E.S.R. (Wintrobe) was 19 mm. in 1 hour. Plasma electrolyte and urea concentrations are shown in Table II. Total serum protein was 6-4 g./100 ml., serum albumin, 3-4 g./100 ml., and globulin, 3.0 g./100 ml. Electrophoretic strip of the plasma showed a slight reduction in the albumin with a normal globulin pattern. Results of plasma and urine steroid estimations are shown in Table II. X-ray of the chest on admission showed a mass in the left lung extending from the hilum into the anterior and posterior segments of the upper lobe. Angiography showed com- plete obstruction of the left innominate vein with reflux into the left internal jugular vein and tributaries of the left subclavian. There was no evidence of obstruction of the right innominate vein. Sputum examination showed the presence of anaplastic (oatcell) carcinoma of the bronchus.
Course in hospital. The clinical, cytological, and radiological evidence indi- cated the presence of a carcinoma of the bronchus producing superior mediastinal obstruction. A tumour dose of 3,684 r over 22 days was directed to the left supraclavicular region and superior mediastinum (Dr. E. W. Emery) which resulted in some improvement in her voice and breathlessness and a decrease in the swelling of her face. The chest X-rays showed a decrease in size of the hilar mass. During treatment with radiotherapy it was noted that she was developing extensive muscular weakness involving her trunk and all four limbs. Her plasma potassium concentration had fallen to 2.6 m Eq./1. and the bicarbonate concentration had risen to 55 mEq./1. At the same time urinary excretion of potassium was 86 mEq./24 hours. At this stage the possibility that the compli- cation of adrenal hyperplasia was present was considered and the urinary 17- ketogenic steroids were measured and found to be 84 mg./24 hours. The plasma cortisol was 59.0 µg./100 ml. at 9 a.m. and 38-4 µg./100 ml. at 12 midnight. A dexamethasone suppression test was performed which showed no suppression of either plasma or urine steroid levels even at a dosage level of 16 mg. a day (see Table III). In spite of potassium supplementation the plasma potassium concentration remained below the normal range; only with the administration of Aldactone-A, together with large doses of potassium tartrate was the plasma
potassium concentration brought within the normal range (Fig. 2). Four weeks after her admission to hospital glucose was detected in her urine for the first time. She subsequently developed polyuria and polydipsia and her fasting blood glucose was found to be 190 mg./100 ml. A glucose tolerance test follow- ing a load of 50 g. of glucose revealed a diabetic glucose tolerance curve, with the maximum height of blood glucose of 380 mg./100 ml. She was given 500 mg.
Dexamethasone mg./d.
16
8
Died
20
KCI
g./d 10
ACTH
80 I.u./d.
Aldactone A 300mg./d.
Plasma K
4
m.Eq/l.
3
17 KGS
120
214
mg./24hr
100
80
60
Plasma
40
Cortisol
ug./1001. 20
9 a.m.
midnight
10
17
24
I
8
15
22
29
R.N. º b. 1907. Apr.
May
1964
of tolbutamide three times a day, but this did not control her diabetes. During her fifth week in hospital she became markedly oedematous and developed a typical Cushingoid appearance of her face. She developed a respiratory in- fection, and produced a purulent sputum. A chest X-ray indicated the break- down and formation of a cavity at the site of the carcinoma. Her condition rapidly deteriorated and she died six weeks after admission which was 10 weeks after the onset of her first symptom.
Autopsy (Professor J. F. Smith) showed a primary oatcell carcinoma probably of the left main bronchus which had broken down into a cavity. The liver contained numerous small metastases. Both adrenals were enlarged and each weighed 16 g. There was no evidence of secondary deposits in the adrenals.
R. C. was a master tailor, aged 56. Five months previously he had a sudden attack of chest pain and an opacity in the right lower lobe was seen on chest X-ray. Sputum examination showed the presence of cells characteristic of oat- cell carcinoma. Both main bronchi were found to be rigid on bronchoscopy. Treatment with radiotherapy was commenced. The development of ankle oedema and rise of blood pressure led to his admission. He had smoked 40 cigarettes daily for many years.
Examination on admission. Dyspnoea on exertion. Gross oedema of both legs, thighs, and sacrum was present, but the venous pressure was not raised. The heart was not enlarged clinically. Blood pressure, 200/105 mm.Hg. The liver was enlarged 5 cm. below the costal margin and its surface was irregular. Ascites was present.
Investigations (see Table II). Chest X-ray showed left lower lobe consolida- tion. Metastases were present in the fifth left rib and multiple metastases were seen in the pelvis.
Course in hospital. The patient became increasingly dyspnoeic and developed bronchopneumonia from which he died nine days after admission. Total course from first observation of oedema to death was 24 days. Autopsy was refused.
S. M., a 59-year old male, first presented in September 1962 with a two months history of productive cough and haemoptysis. X-ray of his chest showed an opacity in the right upper lobe with deviation of the trachea to the left. Bronchoscopy was performed (Miss D. Nightingale) and showed changes con- sistent with a carcinoma of the right upper lobe bronchus. However, a biopsy taken revealed no evidence of carcinoma in the specimen examined. In October 1962 three firm supraclavicular glands were found on the right side and the chest X-ray revealed a considerable increase in size of the opacity in the right upper lobe. The lesion was considered to be inoperable and he was given a course of radiotherapy, following which there was some decrease in the size of the mass. In June 1964 he complained of swelling of his face of two months dura- tion, frequency of micturition, and ankle swelling and was admitted.
Examination on admission. His face was markedly plethoric and red. There was slight muscle weakness. Pigmentation was absent. Blood pressure was 170/100 mg.Hg. Advanced clubbing of the fingers was present. The neck veins were raised on the right. There was dullness and bronchial breathing at the right apex. He had ankle oedema.
Investigations (see Table II). X-ray of the chest showed a marked increase in size of the mass in the right upper lobe.
Subsequent progress. He was given a further course of radiotherapy which produced some decrease in the size of the mass in the right upper lobe. There was no change in the signs of Cushing’s syndrome. The patient refused a further admission to hospital for investigation and possible treatment of his adrenal overactivity. He died at home in November 1964. No autopsy was obtained.
Comment on Clinical Findings (see Table I)
Only two of the nine patients described in the series were females. This is in marked contrast to the sex incidence we have observed, and that which has been reported by others, in Cushing’s syndrome not associated with extra- adrenal neoplasms, where the sex incidence has varied between 3:1 and 9:1 in favour of females. All, except one patient who was 37 years old, were above the age of 48 years. This age incidence is much higher than in Cushing’s syndrome without neoplasms, where the peak incidence is in the third, fourth, and fifth decade of life. Evidence of adrenocortical overactivity in a male over 50 years of age should suggest the possibility of an underlying carcinoma. Five of the nine patients had diastolic blood pressures about 90 mm. of mercury. Only two of the patients in this series had florid signs of Cushing’s syndrome, with the typical moon face and characteristic weight gain. Both these patients and
one other patient without overt signs of Cushing’s disease had diabetes. Muscle weakness was a prominent feature in seven of the cases, while pigmentation was a feature in only two cases. Five of the nine patients had peripheral oedema.
The primary neoplasm was in the bronchus in eight of the nine patients, and in the remaining patient in the parathyroid glands. In seven out of eight cases from whom histology was available, the microscopic picture was that of oatcell carcinoma of the bronchus. In all these patients there were distant tumour metastases.
An autopsy was obtained in five cases. In all of these both adrenals were found to be enlarged and hyperplastic histologically. Tumour metastases were present in the adrenals in two cases. No secondary tumour deposits were discovered either in the region of the pituitary or the hypothalamus.
The longest survival time after diagnosis of the Cushing’s syndrome was four and a half months. Six cases lived less than 18 days after diagnosis of the adrenal hyperactivity. The course was a progressive downhill one in spite of vigorous attempts to correct the hypokalaemic alkalosis. Our clinical impression is that these patients deteriorated and died much more quickly than one would expect from the degree of progression of their carcinoma.
Comment on the Biochemical Findings (see Table II)
Plasma Electrolytes
In all except one patient (D. M.), the initial plasma potassium was below 3.0 mEq./1. (normal range, 3.5 to 5.5 mEq./l.). This is in marked contrast to our observations in 50 patients with non-neoplastic Cushing’s syndrome all of whom had plasma potassium concentrations within the normal range except two patients with levels of 3-4 and 3.0 mEq./1. The only patient in that series with an adrenal carcinoma had a plasma potassium concentration of 3.6 and 4.2 mEq./1. Seven of the nine patients in the present series had an elevated plasma bicarbonate (normal range 23 to 29 mEq./1.); in four of these cases the bicarbonate was above 38 mEq./1. (see Fig. 3). Of the 50 patients with non- malignant Cushing’s syndrome, all 46 in whom this estimation was carried out had plasma bicarbonate concentrations which were within the normal range.
Blood Glucose
Values for fasting blood glucose are available in five patients. Of these, three had elevated levels and were shown to have diabetic glucose tolerance curves. This is a much higher incidence than that observed in the non-neoplastic Cushing’s patients, in whom only seven of the 48 tested were diabetic.
Urinary excretion of 17-ketogenic steroids
The excretion of urinary 17-ketogenic steroids was persistently elevated in all patients. Though repeated estimations were performed in most cases, no normal results were obtained. The results are shown in Fig. 4. The mean of daily urine collections from six patients was 115 mg./24 hours, with a range of
6
:
60
-
5
50
Normal
8
4
40
Plasma K m.Eq./1.
Plasma CO2 capacity m.Eq./1-
3
30
Normal
2
20
-
I
10
320
320
280
280
240
240
Urinary
200
17 keto . steroid excretion omg./24hr 160 . mg/litre
200 Urinary 17 ketogenic steroid excretion 160 omg/24hr .mg./Iltre
·
o
120
·
0
120
80
0
8
o
80
o
8
40
o
8
40
Normal
O.
Normal
o
46 to 156 mg. This contrasts markedly with the findings in the patients with non-neoplastic Cushing’s syndrome where the mean excretion of 17-ketogenic steroids was 20.8 mg./24 hours with a range of 2.6 to 61 mg./24 hours. Forty- two per cent. of the values obtained in that series were within the normal range, fluctuations from day to day being very common.
2140
238
·114
100
g
80
%
Plasma
Il hydroxy
corticoid
concentration
60
pg./100ml
9
9 a.m. midnight
8
40
0
00
20
Normal ranges
9 a.m.
midnight℃
H.B. M.B. M.C. D.M. W.B. R.N. R.C. S.M.
born 1908 1912 1905 1925 1899 1907 1906 1903
8
?
8
8
8
Urinary excretion of 17-ketosteroids
The mean excretion of 17-ketosteroids was 47 mg./24 hours with a range of 3.9 to 111 mg./24 hours (Fig. 4). Only in two patients were normal values obtained at any time. The mean 17-ketosteroid excretion in 45 patients with Cushing’s syndrome due to bilateral adrenocortical hyperplasia not associated with neoplastic disease was 15.2 mg./24 hours with a range of 2.6 to 50 mg./24 hours. One patient with an adrenocortical carcinoma excreted 54 and 104 mg./24 hours.
Plasma 11-hydroxycorticosteroids (plasma cortisol)
The plasma cortisol was found to be persistently elevated in eight patients in whom it was measured. The mean of seventeen estimations performed on eight patients at 9 a.m. gave a mean of 70.1 µg./100 ml. with a range of 37-4- 214 µg./100 ml. (normal 7-26 µg./100 ml.) (see Fig. 5). The diurnal rhythm was lost in five patients in whom the plasma cortisol was estimated at 12 mid- night. The mean of 12 midnight readings in five patients was 79.0 µg./100 ml. with a range of 30.0 to 214 µg./100 ml. (normal < 6 µg./100 ml.) (see Fig. 6). In one patient (R. N.) the plasma cortisol concentration was measured at 9 a.m. and 12 midnight at intervals during the course of her disease and were found to rise progressively with time (see Fig. 7). These results contrast with those obtained in the patients with adrenal hyperplasia without neoplastic disease.
O
80
M.C. 8 b- 1905
Plasma 11 hydroxy corticoid concentration pg./100ml.
R.C. 8 b. 1906
H.B. ₫ b. 1098
10
S.M. Ở b. 1903
I
Normal
9
a.m.
mid night
9
a.m.
mid night
R.N.º b. 1907
21 May 1964
200
160
Plasma Il hydroxy corticoid concentration pg./100ml.
120
Il May 1964
80
40
20 Apr 1964
Normal
9
mid night
am.
Response to corticotrophin
Corticotrophin stimulation tests were performed in two patients, H. B. and R. N., who were given 40 i.u. of corticotrophin gel (of proved biological potency) 12 hourly at 9 a.m. and 9 p.m. for two days. In both there was a fall in the urinary 17-ketogenic excretion on the first and second days of stimulation (see Table III). Little change was observed in the plasma cortisol when measured on each day five hours after the 9 a.m. dose of corticotrophin.
Response to suppression with dexamethasone
Dexamethasone was given in a dose of 2 mg. for two days and increased by 2 mg. daily every two days. The final daily dose reached in two patients was 10 mg. and in another patient 12 mg. In a fourth patient the 8 mg. dose was followed by 16 mg. for one day. In one patient (H. B.) 10 mg. were given for two days only. The results are shown in Table III. In no case was there evidence of complete suppression of either the 17-ketogenic steroids, the 17- ketosteroids, or the plasma cortisol. In one case, however, there was a rise in the 17-ketogenic steroid and 17-ketosteroid excretion. In one patient the 17- ketogenic steroids fell from 77 mg./24 hours to 63 mg./24 hours and in another from 69 mg./24 hours to 63 mg./24 hours. In a further patient there was a fall in the 17-ketogenic steroids from 67 mg./24 hours to 36 mg./24 hours, with a rebound to 163 mg./24 hours on the day after dexamethasone was discontinued.
Cortisol and corticosterone concentrations in the urine
The results of five patients are shown in Table IV. In four of the five patients the urinary cortisol excretion is above the upper limit of normal. In two patients, R. N. and H. B., the levels are markedly elevated. M. C. and H. B. excreted increased quantities of corticosterone. Corticotrophic hormone in- creased the excretion of urinary cortisol in both cases where this was measured. In H. B., 10 mg. of dexamethasone a day for two days has produced a fall in the urinary cortisol and corticosterone. No such fall was observed in M. C.
Discussion
The diagnosis of functional adrenocortical hyperplasia associated with tumours that are not in the adrenals or pituitary presents considerable difficulty because frequently there are no signs or symptoms to suggest the diagnosis of Cushing’s syndrome. Only in two of the patients in the present series was there clinical evidence with the characteristic weight gain, moon face, plethora, and striae. In the majority of our cases this was first suspected by the finding of hypo- kalaemic alkalosis and later confirmed by finding markedly elevated levels of 17-ketogenic steroids in the urine and of 11-hydroxycorticosteroids in plasma from blood taken both at 9 a.m. and 12 midnight. Reliance has, therefore, to be placed on biochemical evidence to make the diagnosis. Final confirmation of the diagnosis was obtained in five of the nine cases at autopsy by the finding of histological evidence of bilateral adrenal hyperplasia.
. The development of adrenal hyperplasia in patients with neoplasms is of prognostic importance as most patients die within a few weeks of the onset of this complication. The cause of death is not altogether clear. Although some die rapidly with widespread metastases, it is our impression that many die much sooner than one would expect from the degree of progression of the primary carcinoma, probably as a result of fulminating adrenal hyperactivity. In one of our patients (H. B.) we were unable to find the primary carcinoma during
| Results of Urinary Cortisol | and | Corticosterone | Concentrations | |||
|---|---|---|---|---|---|---|
| Patient | Treatment | cortisol pg./24-hrs. Total urinary (Normal < 80µg/24-hrs.) | Total urinary (Normal < 20µg/100 ml.) corticosterone pg.|100 ml. | 17-ketogenic steroid mg./24 hrs. | ||
| H. B. | 14/1 | 1,235 | 0 | 146 | ||
| 16/1 | 4,470 | 87 | .. | |||
| 17/1 | Control | 4,440 | 81 | .. | ||
| 20/1 | 2,720 | 59 | ||||
| 22/1 | First day cortico- | 3,580 | 88 | 112 | ||
| trophin | ||||||
| 23/1 Second day cortico- trophin | 3,490 | 82 | 99 | |||
| 24/1 | Control | 2,240 | 20 | 77 | ||
| 26/1 | Dexamethasone 10 mg./ day (day 2) | 514 | 0 | 63 | ||
| 27/1 Control | 1,070 | 0 | 56 | |||
| M. C. | Control | 75 | 0 | 69 on day before | ||
| Dexamethasone (10 mg./day) (day 2) | 159 | 16.5 | 85 (Vol. = 640 ml.) | |||
| Dexamethasone (12 mg./day) (day 3) | 65 | 30-9 | 24 (Vol. only 330 ml.) | |||
| Dexamethasone (12 mg./day) (day 4) | 67 | 10-5 | 63 (Vol. 860 ml.) | |||
| W. H. | Control | 8.6 | 5.8 | 85 | ||
| R. N. | 27/4 | Control | 1,870 | 103 | ||
| 2/5 | Control | 1,320 | .. | 127 | ||
| 5/5 | First day cortico- | 462 | 0 | 59 | ||
| trophin | ||||||
| 6/5 | Second day cortico- trophin | 2,780 | 10-2 | 36 | ||
| 7/5 | Control | 4,920 | 0 | 45 | ||
| R. C. | Control | 38 per litre | .. | 337 per litre | ||
life, in spite of repeated radiological examinations, bronchoscopy, and cytological examination of the sputum. The diagnosis was suspected from the typical electrolyte and steroid changes which were present. At autopsy the primary oatcell bronchial carcinoma was extremely small and it seems inconceivable that its activity could have played a significant part in his death. Polypeptides, other than corticotrophin, may be secreted by the tumour, which were re- sponsible for hastening death in these patients.
The high incidence of bronchial carcinoma in our series fully confirms the findings of others (Allott and Skelton, 1960; Riggs and Sprague, 1961). Oatcell
bronchial carcinomas, pancreatic carcinomas, and thymomas have most fre- quently been described in association with the syndrome of adrenocortical overactivity. These tumours all have histological features in common, and this led Engel and Kahana (1963) to suggest that the association of the syndrome with other tumour types was unacceptable. However, there are numbers of well-documented cases in the literature where the primary carcinoma has not arisen from one of these three anatomical sites. Isolated reports have appeared of the association with carcinoma of the thyroid (Hokfelt, Sjogren, and Falk- heden, 1959), prostate (Webster, Touchstone, and Suzuki, 1959), ovary (Nichols, Warren, and Mantz, 1962; Parsons and Rigby, 1958), colon (Warren, 1945), sympathicoblastoma (Kaplan, Sokaloff, Murray, and Stevenson, 1949), semi- noma of the testis (Di Ferrante, Magliocca, Natali, and Zilli, 1951), breast (Prunty, Brooks, Dupré, Gimlette, Hutchinson, McSwiney, and Mills, 1963), trachea (Bornstein, Nolon, and Bernanke, 1961), and bronchial carcinoids (Escovitz and Reingold, 1961). In patient M. B. in the present series, the primary neoplasm was of the parathyroid glands, and carcinoma preceded the development of the adrenocortical hyperactivity by two years. The diagnosis here was made only when the patient refused all therapy. When her large dose of cortisone was stopped abruptly, instead of adrenal suppression and evidence of adrenal insufficiency being found, her plasma cortisol was in fact found to be elevated and she had a hypokalaemic alkalosis. At autopsy the adrenal glands were four times the normal size. This appears to be the first instance of Cushing’s syndrome associated with a parathyroid carcinoma. Cushing’s syndrome of the non-malignant type has been described in association with hyperparathyroidism (Dent, 1962; Racker, Henneman, and Graf, 1962; Ross, Marshall-Jones, and Friedman, 1966).
In contrast with classical non-malignant Cushing’s syndrome, hypokalaemic alkalosis is almost the rule in Cushing’s syndrome associated with malignancy. There are, however, a number of notable exceptions where the plasma potas- sium and bicarbonate concentrations have been within normal limits (Rosenthal, 1957; MacPhee, 1959; Billinghurst, Thould, Galpin, and Hinton, 1961; Daly, Nelson, and Rose, 1963; Friedman, Mikhail, and Bhoola, 1965). The degree of hypokalaemia is closely related to the increase of adrenocortical function, the lowest plasma potassium concentration occurring in patients with the highest output of adrenal steroids. Prunty and his colleagues (1963) demonstrated that there was a relationship between the cortisol secretion rate and the level of plasma potassium concentration in all forms of Cushing’s syndrome. However, in Cushing’s syndrome associated with extra adrenal neoplasms the mean cortisol secretion rate was three times higher than in orthodox Cushing’s syndrome. The evidence seems to point to an excessive renal loss of potassium due to excessive cortisol concentration as a likely explanation for the hypokalaemia. Differences in the degree of adrenocortical overactivity may be the explanation for the occurrence of cases in which the plasma potassium concentration is within normal limits. There is no evidence to suggest that excess aldosterone secretion plays a part in the production of hypokalaemic alkalosis. With one
exception (Webster, Touchstone, and Suzuki, 1959), aldosterone has been found to be normal or low in the cases where this has been measured (Riggs and Sprague, 1961; Prunty, Brooks, Dupré, Gimlette, Hutchinson, McSwiney, and Mills, 1963).
Meador, Liddle, Island, Nicholson, Lucas, Nuckton, and Luetscher (1962) and Liddle, Island, Ney, Nicholson, and Shimizu (1963) have detected an elevated level of corticotrophin-like substance in the plasma of patients with Cushing’s syndrome associated with extra adrenal malignancy, by means of an assay of corticosterone in adrenal vein blood in hypophysectomized rats following in- jection of the patient’s plasma. Similar findings have been reported by Holub and Katz (1961) and Christy (1961). Corticotrophin-like material has also been extracted from an oatcell carcinoma of the bronchus by Meador, Liddle, Island, Nicholson, Lucas, Nuckton, and Luetscher (1962), Marks, Russfield, and Rosen- baum (1963), and Jarett, Lacy, and Kipnis (1964). Nichols, Warren, and Mantz (1962) extracted a similar material from an ovarian tumour and Engel and Kahana (1963) from a mediastinal tumour. Furthermore, there are reports of the remission of the Cushing’s syndrome when the primary tumour has been removed, with recurrence of adrenal overactivity when the primary tumour had recurred (Engel and Kahana, 1963; Micić and Arsenijević, 1963; Mičić, 1964). Bilateral adrenalectomy has led to relief of the Cushing’s syndrome (Brenton, 1963). Hypophysectomy has had no effect on the degree of adreno- cortical overactivity (Liddle, 1964).
All the evidence points to the primary tumour producing a chemical substance with corticotrophin-like activity. It is suprising that apparently undifferentiated anaplastic oatcells are able to produce such a complicated polypeptide. Cortico- trophin is made up of some 39 amino-acids. It is not necessary to postulate that the complete amino-acid sequence is synthesized by the tumour cells. Cortico- trophin-like activity can be shown by a molecule as small as 13 amino-acids (Guttman and Boissonnas, 1959). It is conceivable that some of the anaplastic cells may revert to a primitive multipotential cell capable of producing various complex chemical substances. This may account for other metabolic disturbances in non-endocrine tumours that closely mimic the actions produced by anti- diuretic hormone, parathormone, thyroid-stimulating hormone, and gonado- trophin.
The ‘corticotrophin-producing’ tumour is autonomous and unresponsive to the normal regulating mechanisms that control the production of adrenocortical hormones. In four of the cases in the present series suppression of corticotrophic activity did not occur during administration of large doses (10 mg. or more) of dexamethasone. In one case there was a surprising rise in urinary 17-ketogenic steroids during dexamethasone administration. Response to exogenous cortico- trophin produced no further rise in the already elevated plasma cortisol levels and urinary excretion products. In the ‘early case’ of this syndrome described by Friedman, Mikhail, and Bhoola (1965) there was some evidence of response to exogenous corticotrophin and only minimal suppression after 8 mg. of dexa- methasone for two days when the 17-hydroxycorticoids fell from control levels
of 45 mg./24 hours to 30 mg./24 hours, with similar changes in the plasma cortisol concentrations.
Distinction must be made between increase in weight of the adrenal glands and increase in functional activity. Nine per cent. of patients with bronchial carcinoma have been found at autopsy to have adrenal glands whose weight was above normal (Sholiton, Incze, and Werk, 1961). Marks, Anderson, and Liberman (1961) reported a case of epidermoid carcinoma of the lung without Cushing’s syndrome, but with an exaggerated plasma cortisol response to cortico- trophin. At autopsy bilateral adrenocortical hyperplasia was found. Belsky and Marks (1962) reported exaggerated plasma cortisol response to cortico- trophin in patients with bronchogenic carcinoma, some of whom had normal adrenals at autopsy. Hymes and Doe (1962) and Werk, Sholiton, and Marnell (1963) have found a similar increased response to exogenous corticotrophin and have found an inverse relationship of this response to length of survival. Nichols and Gourlay (1963) reported two cases of carcinoma of the lung without biochemical evidence of Cushing’s syndrome, but with bilateral adrenal cortical hypertrophy at autopsy. Both tumours were found to be devoid of any substance with corticosteroid-releasing capacity. However, from both tumours a substance was extracted that maintained adrenal weight in hypophysecto- mized animals. They, therefore, postulated the existence of two distinct types of ‘corticotrophin’, one that maintained adrenal weight and another that re- leased steroids. Stack-Dunne and Young (1951) had previously found differences in the adrenal weight maintaining and adrenal ascorbic acid depleting capacity of different commercial corticotrophin preparations.
The finding of adrenocortical hyperactivity in patients with neoplasms carries an extremely poor prognosis for life. If the tumour is operable or amenable to treatment with radiotherapy, this is probably the treatment of choice. Tem- porary relief of the Cushing’s syndrome has been reported when this was possible. An alternate form of treatment would be to direct the therapeutic approach to the adrenal. Metyrapone, which acts by inhibiting the steroid 11 8-hydroxy- lase system, has been tried unsuccessfully in one patient (Clin. Path. Conference Postgrad. Med. School, 1964). Ortho-para D.D.D., which suppresses synthesis of adrenal steroid in man and animals (Vilar and Tullner, 1959; Moy, 1961), has not, to our knowledge, been used in malignant Cushing’s syndrome, but may prove to be of some use. Meta-para D.D.D. was used by Nichols, Warren, and Mantz (1962) in a patient with carcinoma of the ovary and adrenal hyper- activity. They obtained a partial response to this form of therapy. Bilateral adrenalectomy has been performed in one case (Brenton, 1963) with some degree of success. Our own attempt at bilateral adrenalectomy proved unsuccessful. One of the difficulties encountered is that by the time the diagnosis is made the patient is so extremely ill from the effects of severe adrenal overactivity that surgery becomes hazardous. If the diagnosis could be established earlier in the disease, before severe hypokalaemic alkalosis develops, this may become a practical form of therapy. The prognosis then would probably be that of the primary carcinoma without the additional harmful effects of the excessive
steroid production. Such a diagnosis could only be made by biochemical in- vestigation of all patients with oatcell carcinoma of the bronchus.
We are grateful to the following physicians for allowing us to study their patients: Professor M. L. Rosenheim (patient R. N.), Professor C. E. Dent (patients H. B. and M. B.), Dr. P. J. D. Heaf (patient W. H.), Miss D. Nightingale (patient S. M.), and Dr. E. W. Emery (patients R. C. and S. M.). We are particularly grateful to Professor M. L. Rosenheim and Professor C. E. Dent for their help. We would like to thank the Medical Research Council for support given to one of us (M. F.). This work is in part also supported by the British Empire Cancer Campaign.
Summary
Nine cases of Cushing’s syndrome associated with non-adrenal-pituitary malignant neoplasms are described. The findings are compared and contrasted with 50 cases of non-malignant Cushing’s syndrome previously described. In eight cases the primary carcinoma was bronchogenic in origin, whereas in one case the primary arose in the parathyroid glands. Eight of the nine cases pre- sented with a hypokalaemic alkalosis and all were found to have markedly elevated urinary 17-ketogenic steroids and plasma 11-hydroxycorticosteroids, both at 9 a.m. and at 12 midnight. The possible mechanisms producing excess adrenocortical activity are considered. The therapeutic approach to the management of cases with the syndrome is briefly discussed.
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