Adrenocortical Hyperfunction Associated with Bronchogenic Carcinoma: Report of Five Cases
M. H. GAULT, M.D., M.Sc.,” R. BILEFSKY, M.D., t T. D. KINSELLA, M.D., F.R.C.P.[C]# and A. ARONOFF, M.D., F.R.C.P.[C], F.A.C.P., § Montreal
ABSTRACT
Five patients with bronchogenic carcinoma associated with adrenocortical hyperfunc- tion are described. The clinical features, laboratory studies and autopsy findings are discussed and compared with previously reported cases. Four patients presented most of the typical features of this dis- order as previously described, whereas the fifth was atypical in some respects. Typical features included: acute onset of adreno- cortical hyperfunction in a middle-aged male, rapid downhill course, slight or absent physical signs of Cushing’s syn- drome, frequently impaired glucose toler- ance, markedly elevated plasma and urinary 17-hydroxycorticosteroids not suppressed by exogenous steroids, absent diurnal varia- tion of plasma corticoids, hypokalemic alkalosis with normal aldosterone excretion, and tumour histology of the oat cell variety. The adrenal glands of two patients were of normal or slightly increased weight, and mean 17-ketosteroid excretion values were normal in three; this contrasts with the marked increase in adrenal weight and 17- ketosteroid excretion in most reported cases.
I TN 1928 Brown1 first described a patient with Cushing’s syndrome associated with broncho- genic carcinoma. During the past few years this association has been reported with such increasing frequency2-17 that it can no longer be considered due to chance. At least 60 cases have been reported, 34 being described in the papers by Bornstein, Nolan and Bernanke,8 Liddle et al.2 and Prunty et al.17
The tumours are almost always anaplastic, particularly of the oat cell variety,2, 6, 8, 14, 16-18 and as this group comprises only about 9% of broncho-
SOMMAIRE
Les auteurs rapportent cinq cas de cancer bronchogénique accompagné d’hyperfonc- tionnement cortico-surrénal. Ils exposent les faits cliniques, les analyses de laboratoire et les trouvailles à la nécropsie et les com- parent à des cas déjà publiés. Quatre malades présentaient la majorité des traits typiques de la maladie, déjà décrits, tandis que le cinquième était, à certains égards, atypique. Parmi les caractéristiques typiques on notait: début soudain d’un hyperfonc- tionnement cortico-surrénal chez l’homme d’âge moyen, détérioration rapide de l’état général, signes physiques du syndrome de Cushing légers ou absents, présence fré- quente d’une altération de la tolérance au glucose, concentrations plasmatiques et urinaires notablement élevées de 17- hydroxycorticostéroïdes, que des corti- coïdes exogènes ne parvenaient pas à supprimer, absence de variation diurne des corticoïdes plasmatiques, alcalose hypo- kaliémique avec excrétion normale d’aldosté- rone et, enfin, tumeur qui, histologique- ment parlant était du type épithéliome à petites cellules. Les glandes surrénales de deux des malades étaient ou normales ou d’un poids légèrement supérieur à la normale et le dosage moyen des 17-cétosté- roïdes éliminés était normal chez trois malades. Cette dernière constatation est en opposition avec l’augmentation marquée du poids des surrénales et de l’excrétion des 17-cétostéroïdes dans la plupart des cas.
genic carcinomas19 a cellular specificity might be implied.
The isolation of an adrenocorticotrophic material, biologically and physiochemically similar in many respects to ACTH, from the tumour tissue, meta- stases and the plasma of such patients by Liddle et al.2 and others,20, 21 was a major break-through in the understanding of the pathogenesis of this syndrome.
Adrenocortical hyperfunction has also been re- ported in association with tumours of the thymus, prostate, breast, ovary, testis, pancreas, mediasti- num, trachea, gallbladder, parotid, uterus, thyroid, kidney, nervous system and stomach, and with pheo-
From the Departments of Medical Chemistry and Medicine, Queen Mary Veterans’ Hospital, Montreal, Quebec.
This study was supported in part by Department of Veterans Affairs research grant 12-62.
*Director of Medical Chemistry, Queen Mary Veterans’ Hos- pital ; Research Assistant, McGill University Clinic, Royal Victoria Hospital.
+Clinical Fellow, Department of Medicine, Royal Victoria Hospital ; formerly, Senior Assistant Resident, Queen Mary Veterans’ Hospital.
¿Consultant in Medicine, Queen Mary Veterans’ Hospital. §Consultant in Medicine, Queen Mary Veterans’ Hospital ; Demonstrator in Clinical Medicine, McGill University.
chromocytoma and bronchial adenoma.2, 4, 8, 18, 50, 55 While this is a heterogeneous group of neoplasms and some of the associations may have occurred on a chance basis, nevertheless an adrenocortico- trophic material has been isolated from a pheo- chromocytoma, a mediastinal tumour, an islet cell carcinoma, and a parotid carcinoma, each asso- ciated with Cushing’s syndrome.2 The synthesis of a material not normally produced by a given cell type has profound implications for the biochemist and cancer biologist concerning the mechanisms whereby the selection of compounds synthesized by a given cell type occurs. Neoplastic transforma- tion apparently may alter regulatory mechanisms controlling the expression of DNA, so that syn- thesis of peptides and proteins ordinarily repressed may occur.
We wish to report five further cases of broncho- genic carcinoma associated with adrenocortical hyperfunction. Four patients illustrate most of the typical features of this syndrome, whereas the fifth was atypical in some respects.
CASE REPORTS
The most important clinical features, laboratory and pathological findings and methods22-29 are presented in Tables I and II. Plasma and urinary corticoids and urinary 17-ketosteroids of Cases 1 to 4, with response to dexamethasone in Cases 1 to 3, are shown in Fig. 1. This information for Case 5 has been reported in a previous publication.30
CASE 1 .- M.V., a 48-year-old man, was admitted on August 7, 1962, with a four-month history of cough, expectoration, night sweats, exertional dyspnea, left posterior chest wall pain and weight loss of 20 lb. He had also noticed the gradual onset of easy fatigability, generalized muscular weakness, and swelling of his feet and ankles. Physical examination revealed a blood pressure of 120/80 mm. Hg, a pulse rate of 128/min., abnormal signs over the left upper lobe of the lung, a moderate degree of muscle wasting and pedal edema. Serum electrolytes and fasting blood sugar were nor- mal. A chest radiograph revealed a prominence of the left hilar shadow. Biopsy from the left main bronchus later showed an oat-cell carcinoma.
By the twentieth day of hospitalization he had become pale, cachectic, and moderately dyspneic at rest, and had profound muscular weakness. The serum potassium had fallen from 3.6 to 2.8 mEq./1. and the arterial pH was 7.52; chlorthalidone, 100 mg. daily, and meralluride, 2 ml. on two occasions, had been given during the four days prior to demonstration of the hypokalemic alkalosis, accompanied during the last two days by a dietary potassium supplement. A glucose tolerance test showed a fasting blood sugar of 140 mg./100 ml., and one-half hour, one-hour, two- hour and three-hour blood sugars were 230, 288, 250 and 200 mg./100 ml., respectively. Despite treatment with 15 units of NPH insulin daily, 5-fluorouracil, cyclophosphamide and oral potassium, his condition deteriorated rapidly during the subsequent 13 days and he died suddenly on the thirty-third hospital day
while receiving dexamethasone 9 mg./24 hr .; a dose of 3 mg./24 hr. had failed to suppress the elevated plasma and urine 17-hydroxycorticosteroids.
At autopsy, a 7 x 12 cm. tumour extended from the left main bronchus to surround the aortic arch. Gross secondary deposits were present in thoracic and ab- dominal lymph nodes, the liver and esophageal wall. The adrenals weighed 8 g. each and their cortices contained focal microscopic neoplastic deposits. Tumour histology was uniformly oat cell in type.
CASE 2 .- N.W., a 43-year-old man, was admitted on March 25, 1963, with a three-week history of cough, expectoration and swelling of his legs. In mid-February he had suddenly developed diplopia; investigation had failed to elucidate the etiology of his left abducens nerve paresis. Physical examination revealed a blood pressure of 130/80 mm. Hg, a pulse rate of 60/min. and coarse rales over the middle lobe of the right lung. The liver edge was three inches below the right costal margin, and pitting edema was present up to the knees. The left abducens nerve paresis persisted and ecchymoses were seen over the right ankle and left eyelid. His hemoglobin was 10.3 g./100 ml. and his blood sugar (three-hour post- prandial), 106 mg./100 ml. A chest radiograph re- vealed an infiltrative lesion in the right middle lobe. Subsequently, right scalene node and bone marrow biopsies showed metastatic carcinoma.
The serum potassium was 2.8 mEq./1. on hospital day 9, and the CO2 combining power one week later, after administration of potassium supplements, was 31 mEq./1. By hospital day 18, Cushingoid facies, fever, restlessness, dyspnea, chest pain, hemoptysis and ascites had developed. He died suddenly on the twenty-second hospital day shortly after commencing dexamethasone 8 mg./24 hr. Plasma and urine 17- hydroxycorticosteroid values were markedly elevated.
At autopsy, a tumour was found extended from the right middle and lower lobe bronchi towards the periphery of the lung. Gross metastases were present in the mediastinal and mesenteric lymph nodes, liver, pancreas, adrenals and capsule of the pituitary gland. The adrenals weighed 12 g. each. The tumour histology was uniformly oat cell in type.
CASE 3 .- H.B., aged 47, was admitted on December 11, 1961. In early November, he had developed a dry cough and subsequently noticed the gradual onset of increasing thirst, urinary frequency and numbness of his fingers and toes. Left anterior chest pain, increasing dyspnea and swelling of his legs developed two weeks before admission. His mother had diabetes mellitus. Physical examination revealed a dehydrated and con- fused white man with a blood pressure of 170/90 mm. Hg, pulse 88/min. and respirations 40/min. There was evidence of a left pneumothorax, and pitting edema was present up to the knees. Urinalysis showed 4-plus acetone and a random blood sugar was 366 mg./100 ml. Serum electrolytes and CO2 combining power were normal. A chest radiograph revealed a left-sided pneu- mothorax, and water-sealed drainage was instituted. Subsequent tomography and bronchoscopy showed complete occlusion of the left upper lobe bronchus. The hyperglycemia and acetonuria responded to 220 units of crystalline zinc insulin and two litres of normal saline given over the next 12 hours; however,
his CO2 combining power rose from 25 to 38 mEq./1. and the serum potassium fell from 4.8 to 3 mEq./1. Two weeks later these values were 45 and 2.1 mEq./1., respectively.
During the subsequent two months the dominant clinical features were: inability to re-expand the left lung, marked generalized weakness, muscle wasting, particularly of the hands, persistent edema of the lower extremities, the appearance of moon facies, a “buffalo hump” and scattered petechiae. The diabetes was difficult to control, 60 to 150 units of crystalline zinc insulin being required daily. The hypokalemic alkalosis became increasingly resistant to therapy, re- quiring an average of 500 mEq. of potassium chloride per day during the last week of life. Dexamethasone 9 mg./day failed to suppress the markedly elevated plasma and urine 17-hydroxycorticosteroid values. Terminally, he had bronchopneumonia and pulmonary edema.
At autopsy, tumour tissue had replaced the left upper lobe of the lung. Secondary deposits were present in the visceral pleurae, the peribronchial lymph nodes and the liver. The right adrenal weighed 35 g. and the left 40. Tumour histology was uniformly of the oat cell type.
CASE 4 .- J.G., aged 36, was admitted on June 7, 1957. For two months he had suffered from easy fatigability, weakness, dyspnea, swelling of his feet and cough with hemoptysis. He had lost 6 lb. Physical examination revealed a blood pressure of 180/100 mm. Hg, and absent breath sounds with dullness over the left upper chest. The liver edge was felt four inches below the costal margin and edema of the lower extremities up to the mid-calves was present. A papular erythematous rash was seen over the upper chest. Several bruises were noted. The serum potassium was 3.2 mEq./1. and the CO2 combining power was 51 mEq./1 .; glucosuria was absent. A chest radiograph showed a homogenous density involving the left upper lobe, and a bronchogram failed to fill the bronchus to this area.
After a course of nitrogen mustard, prednisone, oral potassium and mercurial diuretics, his appetite im- proved, he gained 40 lb., his edema subsided and his face became rounder. When prednisone and potassium were discontinued, clinical deterioration with progres- sive weight loss and asthenia developed. Following thoracotomy two weeks before death, for drainage of a large necrotic cavity in the left upper lobe neo- plasm, the patient developed severe hyperglycemia and acetonuria. Insulin requirements thereafter ranged from 60 to 130 units of crystalline zinc insulin daily. Other dominant features during the final two weeks were: obvious physical signs of Cushing’s syndrome, persistent hypokalemia in spite of potassium supple- ments of over 100 mEq./day, and an unexplained hyponatremia with serum sodium values of 120 to 125 mEq./1. Plasma and urinary 17-hydroxycorticosteroid values were markedly elevated. Terminally, he de- veloped E. coli septicemia and shock.
At autopsy, the upper lobe of the left lung was replaced by cavitating tumour. Gross secondary de- posits were seen in the right lung, peribronchial and mediastinal lymph nodes, liver and right adrenal. Focal microscopic metastases were present in both adrenal cortices, bone marrow and the pars nervosa of pituitary.
The adrenals weighed 30 g. each. Histologically, the neoplasm was uniformly oat cell in type.
CASE 5 .- A detailed case report of patient J.R., aged 50, has been published in a previous communication.30 The principal features were: severe hypokalemic alka- losis, slightly elevated plasma and urinary 17-hydroxy- corticosteroids, normal urinary 17-ketosteroids, absence of diurnal variation of plasma 17-hydroxycorticoids, transient incomplete suppression of adrenal function with 9 mg. of dexamethasone per day, and severe hypercalcemia. The latter was treated with edetate ethylene diaminetra-acetic acid (EDTA), dexametha- sone, peritoneal dialysis and subtotal parathyroidectomy. He also developed renal failure and pancreatitis.
At autopsy, secondary deposits from a right upper lobe neoplasm were present in lymph nodes, liver, kidney and bone. Adrenal weights were not significantly increased. Histologically, the neoplasm was chiefly of a moderately well-differentiated squamous cell type, but also contained areas of an undifferentiated epi- dermoid character.
DISCUSSION
Clinical Features (Table I (A))
The five male patients ranged in age from 36 to 50 years, with a mean of 45 years; this is typical for patients with intrathoracic neoplasm and hy- peradrenocorticism. In the 17 cases of oat cell carcinoma and hyperadrenocorticism reviewed by Bornstein, Nolan and Bernanke8 the average age was 51 years and there was a male preponderance of 13:4, in keeping with the age of onset and sex distribution of carcinoma of the lung. In contrast, the sex incidence in Cushing’s syndrome is 3:1 in favour of females and the average age of onset is 31 years.31 This does not suggest that Cushing’s syndrome predisposes to the later development of carcinoma of the lung.
The presenting complaints varied, but weakness, edema of the lower extremities and cough were common to all. Three had chest pain. One (with severe hyperglycemia) had polyuria and poly- dypsia. Hypertension was mild in one and absent in the other four patients at the time of admission.
In all five cases the duration of illness from onset of symptoms to death was under six months, with an average of four months. The characteristic course in this disorder is significantly shorter than that ordinarily found in patients with oat cell carcinoma, being under three months in many in- stances;8 this compares with an average duration- between the onset of symptoms and diagnosis-of six months in a large series of patients with oat cell carcinoma uncomplicated by Cushing’s syndrome.32 The life expectancy of untreated patients with Cushing’s syndrome in the absence of extra-adrenal neoplasm has been reported to be about five years,33 in contrast to the frequently acute onset and fulminant course in this syndrome.
The characteristic physical signs of Cushing’s syndrome were absent in each patient on admission
| TABLE I. | |||||
|---|---|---|---|---|---|
| Normal range | Case 1 | Case 2 | Case 3 | Case 4 | Case 5 |
| (A) Clinical features | |||||
| Signs of Cushing's syndrome .. . | None | Facies, | Facies, | Facies, hump, | None |
| Blood pressure | 120-140/60-80 5 | Ecchymosis 120-140/60-90 | Buffalo hump 140-170/80-95 | striae, fat pads 140-160/100-110 5 | |
| 160-190/70-85 | |||||
| Duration of illness-months | 2 | 3.15 | 5 | ||
| (B) Biochemistry and hematology | |||||
| CO2 C.P .- range mEq./1. 22-32 | 27-41 | 28-32 | 25-45 | 30-51 | 20-43 |
| Serum K .- range mEq./1. 3.5-5 | 2.9-4.1 | 2.8-3.8 | 2.1-4.9 | 2.3-5.8 | 2.2-6.0 |
| Blood sugars: (a) fasting <100 | 140 | 76 | |||
| (mg.%) (b) 2-hr. PC .... < 110 | 250 | 106 (3 hr.) | 366 (random) | 822 (random) | |
| Arterial pH 7.35-7.45 | 7.52 | 7.49 | 7.52 | ||
| Hemoglobin-range g.% 14-17 | 8-16 | 7-11 | 12-13 | 8-16 | 9-13 |
| WBC-range per c.mm. 5,000-10,000 | 1,800-9,950 | 5,150-10,200 | 5,200-7,300 | 1,600-16,300 | 6,800-20,000 |
| Eosinophils-range-% ...... 1-4 | 0-4 | 0-1 | 0-1 | 0-1 | 0-3 |
| Lymphocytes-range-% 10-30 | 20-39 | 19-40 | 4-22 | 1-33 | 8-37 |
| (C) Pathology | |||||
| Adrenal glands:54 | |||||
| Right-(grams) 5.3-6.7. | 8 | 12 | 35 | 30 | 6 |
| Left-(grams) 5.3-6.7 | 8 | 12 | 40 | 30 | 7 |
| Metastases. | Cortical | Cortical | None | Cortical | None |
| (focal, | (small, focal) | (small, focal) | |||
| microscopic) | |||||
| Tumour histology. | Oat cell | Oat cell | Oat cell | Oat cell | Squamous cell |
| Extent of primary tumour | 7 x 12 cm. | Most of right middle and lower lobes | Entire left upper lobe | Entire left upper lobe | Entire right upper lobe |
and only two developed the full-blown appearance, each towards the end of their lives; in one other, Cushingoid facies was noted one week before death. The usual clinical stigmata of Cushing’s syndrome have been observed in only about half of the reported cases.4 It is postulated20 that many of these patients do not survive long enough to de- velop the clinical features of Cushing’s syndrome, that because of the preponderance of males the virilizing effects of adrenal hyperfunction are not evident, and that the weight loss commonly seen in these patients tends to counteract the charac- teristic adiposity of Cushing’s syndrome.
Biochemical Abnormalities
(a) Glucose tolerance (Table I (B))
Impaired glucose tolerance has been fre- quently noted in patients with adrenocortical hyperfunction associated with bronchogenic carci- noma.5, 7, 8, 10, 11 In our Case 1 the hyperglycemia was mild and easily controlled with 15 units of NPH insulin daily. Case 3, who had a family history of diabetes, had severe hyperglycemia with acetonuria which led to his admission. Case 4 developed marked hyperglycemia with acetonuria late in his illness. Daily doses of crystalline zinc insulin ranged from 50 to 150 units in Case 3 and from 60 to 130 units in Case 4, in spite of which control was poor. In contrast, the hyperglycemia of Cushing’s syndrome in the absence of carcinoma is characteristically mild, and less than one-quarter of the patients are reported to have had glycosuria.8 It is also of interest that impairment of glucose tolerance may occur in patients with bronchogenic carcinoma without evidence of Cushing’s syn- drome.5
(b) Hypokalemia and alkalosis (Table I (B) ).
One of the most striking laboratory findings in this group of patients was hypokalemic alkalosis. In Case 3, this was masked on admission, the initial CO2 combining power of 25 mEq./1. pre- sumably being the result of a mixed metabolic alkalosis and metabolic acidosis, the latter due to diabetic ketonemia. The range of highest CO2 combining power values in our five cases was 32 to 51 mEq./1. with a mean of 42 mEq./1 .; arterial pH values in Cases 1, 3 and 4 were 7.52, 7.49 and 7.52, respectively. The range of lowest serum potassium values was 2.1 to 2.9 with a mean of 2.5 mEq./1 .; although Case 1 received diuretics prior to documentation of hypokalemia, the serum potassium of 3.6 mEq./1. on admission, the short period of treatment (four days), and the ad- ministration of supplementary dietary potassium for two days make it unlikely that the diuretics were anything more than a contributing factor in the development of the hypokalemic alkalosis. The severity of the potassium loss which may occur in this syndrome is illustrated by the requirement of nearly 1000 mEq. to correct the potassium deficit in Case 5, and the average daily requirement of 500 mEq. during the last week of life in Case 3 to maintain the serum potassium around 4 mEq./1.
A severe disturbance in electrolyte balance is not the usual course of events in Cushing’s syndrome in the absence of carcinoma. In a series of 33 cases reported by Plotz, Knowlton and Ragan,31 the average CO2 combining power was 29 mEq./l. and only one patient had a level above 40 mEq./1. Similarly, the average serum potassium was 4.2 mEq./1., the determinations ranging from 3.2 to 5.3 mEq./1. Bagshawe14 noted a close correlation be-
| Normal range | Case 1 | Case 2 | Case 3 | Case 4 | Case 5 | ||
|---|---|---|---|---|---|---|---|
| Plasma corticoids22 | |||||||
| Range: | 5-25 (8-9 AM) | 51-70 | 46-58 | 40-90 | - | 15-35 | |
| Mean: | 64 | 25 | 55 | 142 | 28 | ||
| Diurnal | variation: | - | absent | absent | - | absent | |
| Urinary 17-hydroxycorticoids23 | |||||||
| mg./24 hr. | Range: | 3-9 | 13-28 | 17-58 | 13-62 | 29-36 | 6-14 |
| Mean: | 20 | 40 | 36 | 33 | 10 | ||
| mg./g. creatinine29 | Range: | 3-9 | 37-45 | 39-52 | 33-72 | 57-62 | 15-23 |
| Mean: | 40 | 46 | 37 | 60 | 19 | ||
| 17-Ketosteroids24 | |||||||
| mg./24 hr. | Range: | 5-20 | 9.5-26 | 18-68 | 26-44 | 11-23 | 2.5-9 |
| Mean: | 17 | 44 | 33 | 17 | 5.7 | ||
| mg./g. creatinine20. | Range: | 5-20 | 29-41 | 37-57 | 35-46 | 23-37 | 7-16 |
| Mean: | 32 | 48 | 38 | 30 | 11 | ||
| Ketogenic Steroids25 | |||||||
| mg./24 hr. | 9-17 | 60 | 87 | 77 | - | - | |
| Suppression Test | |||||||
| Dexamethasone (mg./24 hr.) | 3 | 8 | 9 | - | 9 | ||
| Response. | No | Not | No | - | Partial, | ||
| suppression | completed | suppression | suppression | ||||
| not sustained | |||||||
| Aldosterone26 (ug./24 hrs.) | 5-15 | 8.5 | 6.0 | - | - | 14 | |
| Estrogens27 (ug./24 hrs.) | 18-35 | 95 | 110 | 72 | - | 64 | |
| Pregnanetriol28 (mg./24 hrs.) | 0.7-2.5 | 1.9 | 2.3 | 1.4 | - | 0.7 | |
| Pregnanediol28 (mg./24 hrs.). | 0.05-2 | 3.9 | 6.1 | 3.2 | - | 1.6 |
tween the occurrence of hypokalemic alkalosis and the presence of neoplasms associated with Cushing’s syndrome: in a series of 111 patients with Cush- ing’s syndrome, he found 23 patients with hypo- kalemic alkalosis, and 21 of these had either an endocrine or non-endocrine malignancy.
The present status of the pathophysiology of the electrolyte abnormalities is unresolved, but the evidence tends to exclude the overproduction of aldosterone as the cause of the severe potassium wasting. With few exceptions,16, 34-36 the urinary excretion of aldosterone, when measured, has been normal or low, as in our Cases 1, 2 and 5. Aldos- terone secretion rates have also been normal,17 and several case reports have shown a low aldosterone content in the adrenals at postmortem examina- tion.8, 37, 38 Christy and Laragh39 and Meador et al.20 have suggested that the severity of hypo- kalemia and alkalosis roughly parallels the plasma levels of cortisol, and Prunty et al.17 found the degree of potassium disturbance to be closely linked to the degree of cortisol oversecretion. However, corticosterone has mineralocorticoid activity,40 and increased secretion of this hormone may be a significant factor in the production of hypokalemic alkalosis. Bornstein, Nolan and Bernanke& found that the corticosterone content of the adrenals of one patient with hyperadrenocorticism and an anaplastic tracheal neoplasm exceeded levels re- ported by Neher41 in patients with Cushing’s syn- drome due to adrenal hyperplasia in the absence of extra-adrenal carcinoma. In addition, Cost42 has reported a patient with hyperadrenocorticism, severe hypokalemic alkalosis and oat cell carcinoma who had markedly increased excretion of corti- costerone and a low cortisol-to-corticosterone ratio as compared to patients with hyperadrenocorticism due to other causes. Perhaps the severe hypo- kalemic alkalosis in our Case 5, who showed less
than the usual increase in plasma and urine corti- sol, was due to excessive corticosterone secretion. (c) Steroid studies (Table II, Fig. 1).
The results of 17-ketosteroid and 17-hydroxy- corticoid determinations have been expressed both as mg./24 hr. and as mg./g. creatinine. Our ob- servations agree with those of Werk, Sholiton and Marnell,13 in that the normal ranges of 17-hydroxy- corticoids and 17-ketosteroids when expressed as mg./g. creatinine are similar to those expressed as mg./24 hr. However, in Cases 1, 4 and 5, both 17-ketosteroid and 17-hydroxycorticoid values, when expressed as mg./g. creatinine, were con- siderably in excess of those expressed as mg./24 hr. This may be explained by the fact that these three patients had severe weight loss and had creatinine excretions in most instances under 0.80 g./24 hr., as has been reported for many patients with bronchogenic carcinoma during the last five weeks of life;13 pre-terminally their weights were 108, 128 and 80 lb. following losses of 30, 37 and 50 lb., respectively. Available evidence appears to
Case 1 3mg/D.
Case 2
Case 3
Case 4
90.
Smg. D.
9mg/D.
PLASMA 17-OHCS 18%
Day 75 -142pg%
60
30-
0
!
75
URINE
17-OHCS
50
25
0
75
URINE
17-KS
50
25
0
25 26
27
28
29
30
33
DIED
18 19 20 21 2
22
DIED
51 52
62 63 64 65 66 67 68 69 70
68 69 70
HOSPITAL DAYS
DIED
Day 78
- Died
DEXAMETHASONE mg/24hr. Dmg/g.Creatinine ----… Normal limit
indicate that there is a positive correlation between excretion of creatinine and conjugated 17-hydroxy- corticoids,13, 43-45 cortisol secretion rate44 and 17- ketosteroid excretion.13 If the implication that steroid output varies with lean body mass is correct, the use of a steroid: creatinine ratio might provide a better index of adrenal function in the patient who has had considerable weight loss, as has been suggested in the overweight patient.45 The ratio also provides at least partial compensation for urine collection inaccuracies; there is some question as to completeness of all collections in our Case 1.
Urinary 17-ketosteroids expressed as mg./24 hours showed elevation of mean values in Cases 2 and 3 to about twice the upper normal limit. Mean values for the other three patients were normal, in contrast to the marked elevation usually observed.2, 6, 8 These results are, however, in keep- ing with the findings of Brooks et al.,46 who re- ported that four of seven patients with bronchial tumours and Cushing’s syndrome had 17-ketoster- oid values between 10 and 16 mg./24 hr. When values were expressed as mg./g. creatinine, all of our patients except Case 5 showed consistently elevated values with means of 50% or more above the upper limit of normal. There was some over- lap, on individual days, with the values found by Werk, Sholiton and Marnell13 for patients with bronchogenic carcinoma but without evidence of Cushing’s syndrome, for our Cases 1, 3 and 4, and in all instances for Case 5.
Urinary 17-ketogenic steroid excretion was markedly elevated, being above 60 mg./24 hr. in all three of our cases (1, 2 and 3) tested.
Mean urinary 17-hydroxycorticoid values ex- pressed as mg./24 hr., including those obtained during suppression tests, were two to four times the upper limit of the normal range in four pa- tients; in Case 5, the average value was only slightly elevated. When expressed as mg./g. creatinine, values were comparatively higher in Cases 1, 4 and 5 (as was found for 17-ketosteroids ), being twice the upper limit of normal in Case 5 and four to six times normal in the other patients. This marked elevation is in keeping with that of most other reported cases with this disorder, and is above the range of values found in patients with bronchogenic carcinoma without Cushing’s syn- drome5, 18 (except for Case 5, in which impaired renal function may have played a part in the relatively lower urinary steroid values30).
All patients had consistently elevated plasma 17- hydroxycorticoids, with values almost entirely above 45 µg./100 ml. except for Case 5. The highest value obtained was 142 ug./100 ml. in Case 4. Steroids which compete with cortisol for binding sites on cortisol-binding globulin, chiefly corti- costerone and 11-desoxycortisol ( compound S), are included in the values for plasma 17-hydroxycorti- costeroids.22
Diurnal variation (8 to 9 a.m. and 6 to 7 p.m.) was absent in the three patients for whom such data were available; however, this variation may be reduced or absent in some patients with bronchogenic carcinoma without evidence of Cushing’s syndrome.5, 47
Lack of suppression of cortisol hypersecretion with exogenous steroids has been found to be typical of patients with Cushing’s syndrome asso- ciated with tumours arising from “non-endocrine” tissue.2, 6 This contrasts with a suppression of 50% or greater in urinary 17-hydroxycorticoid excretion ordinarily seen in Cushing’s syndrome due to bi- lateral adrenal hyperplasia when the patient re- ceives dexamethasone 8 mg. daily,48 and implies failure to inhibit ACTH production, presumably because of its origin from the tumour. Pituitary ACTH content has been found to be low.20 A suppression test with dexamethasone was started in four of our patients but was completed only in two. Case 1 showed no significant suppression with 3 mg./day and died during the first 12 hours of the 9 mg./day test. Case 2 died suddenly 36 hours after dexamethasone 8 mg./day was started. Case 3 showed an unexplained increase in both plasma cortisol and urinary 17-hydroxycorticosteroids while receiving dexamethasone 9 mg./day. Case 5 had a fall of about 50% in plasma and urinary 17- hydroxycorticoids (mg./24 hr.) on dexamethasone 9 mg./day, but values rose to near control levels by the time dexamethasone was discontinued, and the urinary 17-hydroxycorticoids, expressed as mg./g. creatinine, did not fall significantly; the marked decline in renal function and the initiation of peri- toneal dialysis during the period of suppression complicate the interpretation in this case. Partial suppression of 17-ketogenic steroids, 17-hydroxy- corticoids or 17-ketosteroids has been reported previously in patients with Cushing’s syndrome associated with malignant bronchial tumours.18, 46, 49
Urinary pregnandiol was elevated in three of four and estrogens in all four of the patients tested. These elevations are considered consistent with the degree of adrenocortical hyperfunction observed. Urinary excretion of aldosterone was normal in all three patients in whom the determination was made.
Response of 17-hydroxycorticoids to ACTH stimulation6, 7, 20 and to the 11-8-hydroxylase in- hibitor, metyrapone (Metapirone),7, 50 has been variable. Adrenalectomy14, 20, 50 and radiation50 have been reported to result in remission of the Cushing’s syndrome.
Pathology (Table I (C))
The range of combined adrenal weights in our five patients was 13 to 75 g .; only values for Cases 2, 3 and 5 (24, 75 and 60 g.) were in the range found in most case reports of bronchogenic carci- noma and hyperadrenocorticism: In Bornstein’s study8 the combined adrenal weights reported in
Canad. Med. Ass. J. Dec. 11, 1965, vol. 93
10 patients ranged from 23 to 86 g. This contrasts with the finding of Symington et al.51 that 91% of 99 patients with Cushing’s syndrome and “normal” or hyperplastic glands unassociated with neoplasia had combined adrenal weights of less than 24 g. They noted that 36% of their patients had adrenal glands whose weights were within the range of normal, although they had been demonstrated to respond abnormally to physiological amounts of ACTH and to have a high steroid 11-8-hydroxy- lating capacity. While the combined adrenal weights in our Cases 1 and 5 were only 16 and 13 g. respectively, a few cases of bronchial tumours associated with Cushing’s syndrome have been re- ported with adrenal glands either of normal size or without notable hyperplasia.17, 52, 53
Metastatic deposits in the adrenals were present in three of our patients. Characteristically about 50% of these patients have cortical metastases.4
Histologically the largest glands (Cases 3 and 4) showed marked nodular cortical hyperplasia, mainly confined to the zona fasciculata, with resultant thin- ning of the zona glomerulosa and distortion of the zonal architecture. The zona reticularis showed inconstant thinning in some areas. These histologi- cal features are considered typical for this group of patients.6 Cases 1 and 2 showed similar features but to a lesser degree.
The four typical cases in this group had tumours of the oat cell variety. In Case 5, which was atypical in some respects, the tumour was histo- logically squamous cell in type, with some poorly differentiated areas. In almost all reported cases of Cushing’s syndrome occurring in association with bronchogenic carcinoma, the tumours have been of the oat cell or undifferentiated cell type;2, 6, 8, 14, 16, 18 however, Prunty et al.17 included a case of squamous cell carcinoma with some poorly differ- entiated areas in their series.
Pituitary metastases are occasionally seen in this group of patients6 and were present in Cases 2 and 4; however, in Case 2 there was only involve- ment of the capsule, and in Case 4, of the pars nervosa. Hyaline changes in the basophils of the anterior pituitary were not present.
SUMMARY
Five patients with bronchogenic carcinoma associated with adrenocortical hyperfunction are reported. This association should be suspected when a patient who presents with such a neoplasm, or with Cushing’s syn- drome, has one or more of the following: an un- explained rapid downhill course, appreciable edema, more than mild impairment of glucose tolerance, and, especially, moderate or severe hypokalemic alkalosis. In the absence of a primary adrenal tumour, markedly elevated plasma and/or urinary 17-hydroxycorticoids not suppressed by large doses of exogenous steroids strongly support the diagnosis. In general, the same features should suggest Cushing’s syndrome when ob- served in the presence of other extra-adrenal tumours which may also demonstrate this observation.
We are indebted to Dr. M. M. Hoffman for his construc- tive review of the manuscript; to the staff of the clinical investigation unit, Queen Mary Veterans’ Hospital, and to Dr. E. Venning for performing certain steroid determina- tions; to Dr. J. Darragh and Dr. M. Aronovitch for the opportunity to study their patients; to Dr. A. Jean and Dr. W. Pirozynski for assistance in evaluation of the pathology; and to Miss L. Marien for valuable secretarial assistance.
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