THE CANADIAN MEDICAL ASSOCIATION LE JOURNAL DE L’ASSOCIATION MÉDICALE CANADIENNE
JULY 24, 1965 . VOL. 93, NO. 4
Islet-cell Carcinoma (Zollinger-Ellison Syndrome) with Fulminating Adrenocortical Hyperfunction and Hypokalemia
M. C. GEOKAS, M.D., M.Sc.,” J. YOUL CHUN, M.D., M.Sc., J. J. DINAN, M.D., F.A.C.S. and I. T. BECK, M.D., Ph.D., F.R.C.P.[C], F.A.C.P., Montreal
ABSTRACT
The production of ACTH-like material by tumours arising in non-endocrine tissue may initiate severe adrenocortical hyper- function. The pathogenesis and clinical and laboratory features of Cushing’s syndrome associated with such tumours are character- istic. The autonomous production by the tumour of ACTH-like material cannot be suppressed by exogenous corticoids. The onset of clinical symptoms is rapid; muscle wasting, general weakness, thirst and peri- pheral edema predominate, and the classical signs of Cushing’s syndrome may be absent. High levels of plasma 17-hydroxycorti- costeroids and urinary 17-hydroxycorti- costeroids and 17-ketosteroids, usually with normal levels of urinary aldosterone, com- monly occur. Hypokalemic alkalosis unre- sponsive to replacement therapy may cause death. In the case reported herein, the in- triguing possibility exists that two hormone- like substances were produced by the primary growth and its metastases: one, ACTH-like, to account for the adrenal hyperplasia and Cushing’s syndrome; and another, gastrin-like, giving rise to the ulcerogenic diathesis.
A DRENOCORTICAL hyperfunction has been reported in association with all three types of pancreatic neoplasia-acinar, and functioning and non-functioning islet-cell carcinoma.
From the Department of Medicine (Subdepartment of Gastroenterology) and the Department of Surgery, St. Mary’s Memorial Hospital, and the Department of In- vestigative Medicine, McGill University, Montreal.
*Present address: Department of Medicine, Royal Victoria Hospital, Montreal 2, Quebec.
Address for reprints: Dr. I. T. Beck, St. Mary’s Memorial Hospital, Montreal 26, Que.
SOMMAIRE
La sécrétion d’une substance apparentée à l’ACTH, par des tumeurs qui naissent sur des tissus non endocriniens, peut déclencher un hyperfonctionnement cortico-surrénal grave. La pathogénèse, les signes et symp- tômes cliniques et les analyses de laboratoire du syndrome de Cushing qui accompagne ces tumeurs sont très caractéristiques. La production autonome par la tumeur de sub- stance apparentée à l’ACTH ne peut être supprimée par l’administration de corticoïdes exogènes. Les symptômes cliniques apparais- sent rapidement; une fonte musculaire, une faiblesse générale, la soif et un oedème périphérique predominent et les signes clas- siques du syndrome de Cushing peuvent être absents. On constate couramment de fortes concentrations de 17-hydroxycorti- costéroïdes plasmatiques et urinaires et une forte augmentation des 17-cétostéroïdes urinaires, généralement avec des taux nor- maux d’aldostérone urinaire. Une alcalose hypokaliémique qui ne cède pas à la médi- cation de remplacement peut entraîner la mort. Dans le cas publié ici, on envisage la possibilité, assez bizarre, que deux sub- stances apparentées à des hormones seraient produites par la tumeur primaire et ses métastases: l’une d’elles, semblable à l’ACTH expliquerait l’hyperplasie surrénale et le syndrome de Cushing et l’autre, sem- blable à la gastrine, ferait naître la diathèse ulcérogène.
Del Castillo, Trucco and Manzuoli11 in 1950 pub- lished the first report of islet-cell carcinoma of the pancreas associated with Cushing’s syndrome. The patient was a 38-year-old woman who died eight
months after the presence of a pancreatic lesion was suspected; this tumour was found at necropsy. Rosenberg29 in 1956 reported the second case, with fulminating adrenocortical hyperfunction. This 40- year-old woman had an islet-cell carcinoma with hepatic metastases, adrenal hyperplasia and post- operative pancreatitis. Hypokalemia (1.8 mEq./l.) and increased levels of plasma 17-hydroxycorti- costeroids (92 µg./100 ml.), urinary 17-ketosteroids (39-47 mg./24 hours) and 17-hydroxycorticosteroids (41-48 mg./24 hours) were the pertinent findings. The patient had no physical signs of Cushing’s syn- drome. In 1946 Crooke10 reviewed four cases of acinar pancreatic carcinoma with Cushing’s syn- drome and pituitary basophilism. In five cases of adrenal hyperplasia associated with islet-cell tumours of the pancreas and/or multiple endocrine
prandial epigastric pain since 1943. He had noticed tarry stools on several occasions. Radiological examina- tion showed markedly enlarged mucosal folds in the stomach and an ulcer crater in the duodenal cap. He was discharged on a medical regimen.
In 1957 the patient was readmitted because of severe epigastric pain accompanied by nausea and vomiting. His hemoglobin was 14 g. per 100 ml. and his hematocrit was 44%; urine analysis was normal. Serum electrolytes were as follows: sodium, 142 mEq./1 .; potassium, 3.0; CO2, 27.3; and chlorides, 107.8. In May 1957 he underwent subtotal gastrectomy (Billroth II) for duodenal ulcer, and cholecystectomy with exploration of the common bile duct for cholelithiasis. On manual exploration of the pancreas, the ulcer was penetrating and was adherent to the head of the pancreas, which was enlarged, firm and nodular.
| References | Patient | Adrenal glands | Histology of tumour and other features | ||
|---|---|---|---|---|---|
| Age | Sex | Histology | Total weight | ||
| Rosenberg29 | 40 | F | Hyperplasia | 37.5 g. | Islet-cell carcinoma; "diabetic glucose tolerance test" |
| Farrant and Insley14 | 47 | M | "Enlarged" | Not stated | Islet-cell carcinoma; diabetes |
| Balls et al.5 | 36 | F | Hyperplasia | 42.0 g. | Islet-cell carcinoma; hyperin- sulinism |
| del Castillo et al.11 | 38 | F | Not stated | 32.0 g. | Islet-cell carcinoma |
| Meador et al.23 | 47 | F | Hyperplasia | Not stated | Islet-cell carcinoma; diabetes |
| Geokas et al. (this paper) | 59 | M | Hyperplasia | 50.0 g. | Islet-cell carcinoma; ulcerogenic diathesis |
tumours cited by Murphy et al.24 there was no evidence of adrenocortical hyperfunction. Balls et al.5 in 1959 published the first report of Cushing’s syndrome in association with a functioning islet-cell carcinoma that gave rise to terminal hypoglycemia and constant convulsions in spite of large amounts of glucose given orally and intravenously. Finally, in 1962, Zollinger et al.,35 reviewing the problem of ulcerogenic tumours of the pancreas, cited 132 cases, 101 of which had been reported previously in the literature. In 10% of these patients, intract- able diarrhea was said to be the only symptom before they died of hypokalemia. Polyglandular in- volvement occurred in about 25%.
The case described in the following report is con- sidered of particular interest because the patient concerned had a long history of islet-cell carcinoma with profound ulcerogenic diathesis, and sub- sequently developed fulminating adrenocortical hyperfunction with persistent hypokalemic, hypo- chloremic alkalosis two months before he died. This is the fifth report of “non-functioning”* islet- cell carcinoma associated with hypercorticism, an interesting combination of two metabolic abnor- malities in the same patient (Table I).
CASE REPORT
The patient was first admitted to hospital in 1951, when aged 47, with a history of periodic late-post-
The patient’s condition improved for a few months but in October 1958 he again complained of dull, post- prandial epigastric pain with crampy exacerbations, occasionally associated with diarrhea. The pain inter- fered with his sleep and required analgesics. At that time the serum calcium was 8.8 mg./100 ml .; phos- phorus, 3.4 mg./100 ml .; hemoglobin, 16.0 g./100 ml .; and hematocrit, 47%. A glucose-tolerance curve showed a fasting blood sugar of 95 mg. per 100 ml., with blood glucose values of 193, 187 and 98 mg. per 100 ml. at 30, 60 and 120 minutes, respectively. Intravenous cholangiogram and pyelogram were normal; a barium- meal examination showed a large stomal ulcer. The patient underwent revision of his gastroenterostomy stoma with excision of the ulcer, which was on the stomach side of the anastomosis, in the posterior wall of the gastric remnant. Several large lymph nodes were found in the retroperitoneal area; frozen section showed metastatic carcinoma, and the report of a more de- tailed pathological study later suggested that “the metastatic carcinoma in the mesenteric lymph nodes was from a malignant adenoma presumably in the pancreas.” With the clinical picture of intractable and recurrent peptic ulceration, the operative and patho- logical findings, the diagnosis of Zollinger-Ellison syn- drome was entertained.
In 1961 the patient was readmitted because of inter- mittent upper abdominal pain, but he also had signs and symptoms of dumping episodes, such as tachy- cardia, perspiration, weakness, borborygmi and a desire to lie down while eating or shortly after meals. A barium-meal examination showed remarkable coarsen- ing of the mucosal folds of the gastric remnant and of the efferent loop, suggesting “gastrojejunitis”. Also, very
*A change in terminology will be necessary in view of the fact that non-beta-cell tumours produce hormone-like substances, e.g. gastrin.
rapid emptying of the gastric stump and dilatation of the efferent loop were noted.
In June 1963, at the age of 59, he was readmitted because of severe pain in the left upper quadrant, with anorexia, occasional nausea and vomiting, a 23-lb. loss of weight and pedal edema. At that time the hemoglo- bin value was 12.1 g./100 ml., the hematocrit 37%, and non-protein nitrogen 35.6 mg./100 ml. Serum electro- lytes were as follows: sodium, 139; potassium, 4.4; and chlorides, 112.5 mEq./l. The total serum protein was 4.9 g./100 ml .; albumin, 2.5 g .; and globulin, 2.4 g. The arterial blood pressure was 120/80 mm. Hg. On July 5, 1963, a large tumour originating in the tail of the pancreas was removed in two parts. The liver was free of metastases but there was extensive involvement of regional lymph nodes. The histological diagnosis was islet-cell carcinoma of the pancreas with metastases in lymph nodes.
The patient recovered well from the operation but then experienced a new set of symptoms-extreme weakness, with difficulty in getting out of bed, pro- found muscle wasting, pedal edema, excessive thirst and polydipsia. His appetite was fair and dumping symptoms were evident during or shortly after meals. The laboratory findings were most revealing. Total serum proteins were 4.6 g., albumin, 1.9 g., and globu- lin, 2.7 g./100 ml. The fasting blood sugar was 87 mg./100 ml .; serum potassium, 1.7; sodium, 136; CO2, 46.4; and chlorides, 84 mEq./1. Serum calcium was 8.8 mg./100 ml. An attempt was made to correct the hypo- kalemic alkalosis by continuous intravenous infusion of potassium chloride in the order of 80-120 mEq. per 24 hours in a constant drip, and also 2 g. daily by mouth, all without success. The serum potassium value did not rise above 2.3 mEq./1. A spirolactone compound was given for four weeks (Aldactone A, 150 mg. daily in divided doses), also without response. Urine sodium excretion with the patient on an uncontrolled diet varied from 2.1 to 14.0 mEq./1. daily. Potassium excretion varied from 27.5 to 67.8 mEq./1. daily. Urinary 17- ketosteroids were found to be 27.2 mg. per 24 hours (normal range: 3-19),13 and 17-hydroxycorticosteroids 16.7 mg. per 24 hours (normal: 4.5-16).2 The plasma 17-hydroxycorticosteroid value seven days before death was 149 µg./ml. at 8 a.m. and 135 µg. at 4 p.m. (normal range: 6-25 µg./100 ml .; mean: 15 ± 4.5 µg. ).28 Analysis of the urine revealed traces of albumin and a pH of 7.5. In addition to the electrolyte supple- ments, the patient received repeated infusions of plasma, human serum albumin and whole blood. Be- cause of his low-grade fever and production of muco- purulent sputum, chloramphenicol, 2 g. daily, was given intramuscularly for 10 days.
Radiographic examination of the skull revealed multiple sharply defined radiolucent areas representing possible metastatic lesions, but the sella turcica ap- peared normal. In spite of the supportive measures, the patient’s condition deteriorated gradually. He died sud- denly, with abdominal pain, hypotension, tachycardia and cyanosis, 64 days after the second operation and two months after the hypokalemic alkalosis was noted.
AUTOPSY FINDINGS
The pertinent findings were as follows. The primary neoplasm was an islet-cell carcinoma of the pancreas, with metastases in the lymph nodes (regional, para-
aortic and hilar), common bile duct, root of mesentery, epicardium, visceral pleura, bone, spinal column, sternum and ribs. There was marked adrenal hyper- plasia (total weight = 50 g.). A healed stomal ulcer and multiple liver abscesses were found. There was also obstruction by tumour and dilation of the common bile duct, pancreatic duct and inferior vena cava.
MICROSCOPIC FINDINGS
Pancreas .- Sections of the tumour located submucos- ally at the ampulla of Vater revealed moderately desmo- plastic tissue containing small and large nests and cords of medium-sized, relatively uniform, round to polygonal cells, with indistinct cytoplasmic borders. The over-all appearance of the tumour cells resembled closely those of the islets of Langerhans. No specific granules could be demonstrated in the tumour cells in specially stained sections. In the central part of the tumour there were trapped ducts of aberrant pancreatic tissue. Multiple sections of both ends of the pancreas proper revealed no tumour. Therefore, it was concluded that this tumour arose from aberrant pancreatic tissue of the duodenum (Fig. 1).
Metastatic tumours .- All of the metastatic tumours were identical to the primary tumour except that very little or no desmoplasia was present (Fig. 2).
Pituitary gland .- The general architecture was normal. Some of the basophilic cells were considerably enlarged and had “ground-glass” basophilic or slightly eosinophilic cytoplasm with or without vacuoles. A few large basophilic cells had bilobulated nuclei (Fig. 3).
Adrenal glands .- There was a greatly thickened cor- tex consisting of nests, cords and elongated tubules of large eosinophilic, polygonal cells, with round or oval nuclei. The cytoplasm was somewhat granular and con- tained very little or no lipid (Figs. 4a and 4b).
Parathyroid glands .- The four parathyroid glands showed identical structure. Each consisted of solid sheets of chief cells with occasional nests of clear cells. No adipose tissue remained. The histology was consis- tent with a diagnosis of primary chief-cell hyperplasia. Kidneys .- The renal structure was normal. There was no vacuolar nephropathy.
DISCUSSION
During recent years great interest has been aroused by reports of a variety of syndromes, asso- ciated with neoplastic disease, which are not due to direct infiltration of a tumour or its metastases. The site of the primary tumour is not always im- portant, except perhaps in such conditions as secondary polycythemia and pulmonary osteo- arthropathy. One of the most interesting groups of syndromes is that of increased adrenocortical activity associated with malignant tumours in organs not related to pituitary or adrenals. Over 100 cases of this syndrome have been reported in association with carcinoma in various organs (Table II).
| Lungs and tracheobronchial | Parotid gland |
| tree (small-cell carcinoma) | Gallbladder |
| Pancreas (acinar; function- | Kidney |
| ing and non-functioning islet- | Breast |
| cell carcinoma) | Ovary |
| Adrenal medulla (pheochro- | Testis (seminoma) |
| mocytoma) | Prostate |
| Thyroid | Colon |
| Thymus (thymoma, benign and malignant) | Small bowel (carcinoid) Sympathetic chain |
Clinical evidence of Cushing’s syndrome often is lacking in these cases even though blood and urinary levels of corticosteroids are extremely high. Whereas hypokalemic alkalosis is relatively rare in uncomplicated Cushing’s syndrome, it was the pre- dominant feature in 19 of Bagshawe’s3 23 cases of the syndrome in association with neoplasia. In a review of the literature we found that the aldoster- one levels were normal when measured in such cases, except in the following three patients. Farrant and Insley14 reported the case of a 41-year- old man with islet-cell carcinoma, without clinical signs of adrenal hyperfunction but with severe hypokalemic alkalosis, adrenal hyperplasia and in- creased urinary excretion of aldosterone (16 ug. per 24 hours), 17-hydroxycorticosteroids (134 mg. in 24 hours) and 17-ketosteroids (59 mg. in 24 hours). Webster, Touchstone and Suzuki33 de- scribed a 68-year-old man with extensively meta- stasizing carcinoma of the prostate, in whom severe hypokalemic alkalosis developed and in whom the urinary excretion of aldosterone, 17-ketosteroids and 17-hydroxycorticosteroids was increased. Hyperplasia of the zona fasciculata was found at autopsy; the zona glomerulosa was hyperplastic in only a few microscopic foci. Lockwood20 reported a 61-year-old man who had bronchogenic carci- noma of the oat-cell type with metastases to the
liver, mediastinal lymph nodes and adrenals, and who excreted increased quantities of aldosterone in the urine (24 µg. in 24 hours).
Aldosterone studies were not carried out in our patient, but an attempt was made to counteract the possible aldosterone excess by administering a spirolactone derivative-without success, as indicated by the patient’s failure to preserve potassium while receiving this compound, for its excessive urinary loss and the resultant hypo- kalemia remained unaltered. Actually, the gross urinary potassium loss, the severe hypokalemic alkalosis, general weakness, adrenal hyperplasia with high levels of plasma 17-hydroxycorti- costeroids, and the lack of clinical signs of Cushing’s syndrome, were the most striking features in this case.
Hypokalemia .- As mentioned above, hypokalemia has been reported frequently in cases of Zollinger- Ellison syndrome accompanied by intractable diarrhea.27 The clinical symptoms of chronic hypo- kalemia include polyuria, polydipsia, general weak- ness, tetany, vomiting, cardiac abnormalities and psychotic behaviour. The pathological changes associated with chronic potassium loss are most often seen in the kidneys and the heart. The renal lesions are primarily tubular, with vacuolation, pyknosis of nuclei and actual cellular necrosis. Glomerular function also may be somewhat affect- ed, giving rise to slight azotemia and proteinuria. In spite of the renal tubular abnormality, the potassium-deficient kidney is able to preserve po- tassium.7 In our patient, vacuolar changes were not found at autopsy, possibly because of the relatively short duration of hypokalemia and the continuous potassium administration. Myocardial necrosis17 and lymphocytic infiltration have been reported in chronic hypokalemia, with ST- and T-wave changes in the electrocardiogram.
The hypokalemia that develops in Zollinger- Ellison syndrome, with intractable diarrhea, low urinary potassium content and unusually high stool potassium, responds readily to constant intravenous infusion of potassium. It has been said that urinary potassium excretion less than 20 mEq. per day by a patient with hypokalemia exonerates the kidneys as the pathway for depletion.8 In our case the hypo- kalemic alkalosis obviously was due to gross urinary potassium loss, probably because of increased corti- costeroid secretion. Constant intravenous infusion of potassium chloride up to 120 mEq. daily had no effect. It has been suggested that high levels of plasma cortisol might have a strong “mineralocorti- coid” effect due to renal tubular action or release of intracellular potassium.” The correction of the electrolyte disturbance by adrenalectomy in some cases of hypercorticism associated with carcinoma supports this explanation.3
Christy and Laragh,9 in a recent study of 43 pa- tients with Cushing’s syndrome, 12 of whom mani- fested severe hypokalemic alkalosis, demonstrated
a statistical association between the electrolyte de- rangement and the high levels of plasma cortisol. They also indicated that “the secretion of unusual mineralocorticoids could not definitely be ruled out.” In our patient, the level of plasma 17-hydroxy- corticosteroids was high, suggesting a maximal adrenal stimulation by circulating adrenocorti- cotrophic material. It has been said that, in Cush- ing’s syndrome, the normal diurnal variation in plasma cortisol levels does not take place, a very important basis for the explanation of the clinical and biochemical findings.12
Adrenal hyperplasia .- The adrenal cortex may hyperfunction when it is normal or hyperplastic, or is the site of a primary or metastatic carcinoma. Adrenal cortical hyperplasia was found by Parker and Sommers26 in 60 of 1012 necropsies of patients with cancer. Also, adrenal hyperplasia was found in another study in 9 of 100 patients with bron- chial carcinoma.30 Marks, Anderson and Liberman22 reported lung cancer in a 64-year-old man who showed a marked response to ACTH stimulation; clinical features of Cushing’s syndrome were absent and his electrolyte values were normal, but enlarge- ment of the adrenals (total weight, 54 g.) was found at necropsy. Wilens and Plair34 found that hyperplasia of the adrenal cortex was a common finding at necropsy in adult men, particularly past the age of 60, who had no clinical evidence of hormonal abnormality during life. In most of the reported cases of adrenocortical hyperfunction associated with carcinoma of other organs, enlarge- ment of the adrenals with cortical hyperplasia was noted. The hyperplasia involves the zona fasciculata or zona reticularis, or both, and resembles that seen in classical Cushing’s syndrome.1
In a series of 81 cases of classical Cushing’s syn- drome due to cortical hyperplasia reported by Sprague et al.,31 totally removed single adrenal glands weighed between 2.5 and 26.5 g. In 18 cases of adrenocortical hyperplasia related to carcinoma reported by Allott and Skelton,1 the average total weight of the adrenals was 33.5 g .; and in eight with adrenocortical hyperfunction associated mainly with bronchial carcinoma, and with metastatic foci in the adrenals, the average weight of both glands was 26.2 g.4
The role of the adrenal metastases in the produc- tion of adrenocortical hyperfunction is unknown. Nevertheless, the realization that hypercorticism can be associated with primary carcinoma situated else- where is of significant practical importance: a mistaken diagnosis of primary adrenal carcinoma and resultant adrenalectomy may be prevented, and a primary neoplasm elsewhere be suspected. Bag- shawe3 has emphasized that severe hypokalemic alkalosis in a patient with adrenocortical over- activity should arouse suspicion of a primary carcinomatous process, most probably broncho- genic. If no evidence of carcinoma can be found in a patient who has Cushing’s syndrome and severe
electrolyte disturbance, a close follow-up for several months or years seems to be essential.
Pituitary changes .- In classical Cushing’s syn- drome, hyalinization of the basophils (“Crooke’s change”) is a common feature. Kilby, Bennett and Sprague18 described prehyaline degranulation of the basophil cells in patients treated with cortisone and corticotrophin. The same changes were found by Crooke10 in his four cases of carcinoma of the pancreas. Our patient had moderate changes of hyalinization and vacuolization of the basophils.
Mechanism of adrenal stimulation .- A variety of studies have been carried out in the last few years and there is accumulating evidence that an ACTH- like substance produced by different tumours is re- sponsible for the adrenal hyperfunction in these cases. The presence of adrenocorticotrophic ma- terial in tumours removed during operation or at necropsy has been demonstrated by Holub and Katz16 and by Meador et al.23 and Nichols, Warren and Mantz.25 Liddle et al.,19 from consistent data derived from 13 cases of Cushing’s syndrome asso- ciated with non-pituitary tumours, emphasized that a polypeptide similar to ACTH was produced by these tumours and was responsible for the adreno- cortical hyperfunction. The production of ACTH- like material by these tumours is autonomous and, therefore, is not suppressed by exogenous corti- coids.
In view of the accumulating evidence that ulcero- genic tumours of the pancreas are the source of a gastrin-like substance,15, 35 demonstrated by bio- assay of the extracts of islet-cell tumours and their metastases, we find very interesting the possibility that in our patient two hormone-like substances were produced by the same tumour.
Unusual features of the syndrome .- Three per- tinent findings in cases of adrenocortical hyper- function of the tumour group have been empha- sized by previous reports: the rapidity of onset, absence of the classical physical signs of Cushing’s syndrome in some cases, and severe hypokalemic alkalosis. The clinical features of Cushing’s syn- drome were lacking in about one-third of patients, a finding that has been attributed to the rapidity of the course which does not give enough time for the full-blown picture to develop. In such cases the clinical picture is influenced also by the primary tumour and its metastases, with loss of weight, anorexia, muscle wasting, edema, anemia and other biological effects. For instance, weight loss due to primary cancer reduces the appearance of truncal and facial obesity. Actually, in some of the patients, two types of symptoms might be seen-those due to the primary tumour and those caused by the adrenocortical disturbance. Extreme weakness appears to be due to the hypokalemia. Hypertension is an inconstant feature. Hirsuties, loss of scalp hair and sexual disturbances have been reported. Thirst and polyuria were noted in about one-third of the reported cases.
Treatment .- In a few instances the usually fulminating course of this syndrome appeared to have been altered by adrenalectomy. One patient reported by MacPhee21 survived 12 months after a bronchial adenocarcinoma was discovered and two years after adrenalectomy for Cushing’s syndrome was performed. Most of the signs and symptoms of hypercorticism disappeared after the operation. Bagshawe’s patient3 appeared to improve after total bilateral adrenalectomy was performed, with complete regression of the Cushing’s features; electrolyte balance was maintained easily with re- placement therapy (a-fluorohydrocortisone and hydrocortisone) and no electrolyte supplements were necessary although the total exchangeable potassium remained low. In the last few years, several reports have confirmed the favourable effect of an adrenocorticolytic agent, o,p DDD (2,2- bis(2-chlorophenyl-4-chlorophenyl) 1-1 dichloro- thane), in cases of adrenal cortical carcinoma and Cushing’s syndrome. Wallace et al.32 reported two cases of Cushing’s syndrome due to adrenocortical hyperplasia in which clinical improvement was in- duced by the use of this adrenocortical inhibitor, and Nichols, Warren and Mantz25 reported good results in cases of adrenal hyperplasia secondary to ovarian tumour. In our case, the patient died suddenly and no attempt could be made to alleviate his hypercorticism.
SUMMARY
The pathophysiology of adrenocortical hyperfunction associated with carcinoma of various organs is dis- cussed.
A case of islet-cell carcinoma of the pancreas (Zollinger-Ellison syndrome) associated with adreno- cortical hyperplasia and biochemical signs of Cushing’s syndrome is reported. Clinical features of hypercorticism were lacking. Pertinent findings were extreme weak- ness, profound urinary loss of potassium and hypo- kalemic, hypochloremic alkalosis unresponsive to in- tensive therapy. The biochemical disturbance obviously was due to high levels of circulating 17-hydroxycorti- costeroids and their “mineralocorticoid” effect.
A review of reported cases of islet-cell carcinoma associated with hypercorticism is presented. The possi- bility that the primary growth and its metastases in such cases may be the source of ulcerogenic as well as adrenocorticotrophic activity is considered.
ADDENDUM
Since the submission of this paper a similar case has been reported in which ACTH and a gastrin-like substance were isolated from the primary pancreatic tumour (Liddle, G. W. et al .: The ectopic ACTH syndrome. In: Proceedings of the 2nd International Congress of Endocrinology, London, August 1964, Excerpta Medica International Congress Series No. 83, Amsterdam, 1965, p. 489).
We wish to express our appreciation to Dr. J. S. L. Browne for his invaluable suggestions and to Dr. A. Carballeira for reviewing the manuscript.
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Treatment of Infections with Colistimethate Sodium (Coly-Mycin)
K. C. RODGER, M.D., M. NIXON, M.D. and H. O. TONNING, M.D., Lancaster, N.B.
ABSTRACT
Colistimethate sodium (Coly-Mycin) was used in the treatment of 17 patients: 13 had urinary tract infections (two of these had positive blood cultures), three had respiratory tract infections, and one patient had both urinary and respiratory tract in- fections. In nine of the 17 a foreign body- either a carcinoma, a catheter, or a stone- complicated the infection.
The dosage used was 1.1-2.3 mg./lb./day with a maximum in one case of 2.4 g. given over an eight-day period. The organisms so treated included Pseudomonas, six; Aero- bacter, six and E. coli, two. Both Pseudo- monas and Aerobacter were encountered in three cases.
On bacteriological grounds, six patients were cured, eight relapsed, and in three the infecting agent was replaced by another organism, The best responses were obtained in those patients with Pseudomonas infec- tion. Side effects included nausea, vomiting, vertigo, paresthesias, and pain at the site of injection.
Colistimethate sodium has a place in the treatment of Gram-negative infections excluding Proteus organisms.
C OLISTIMETHATE sodium (Coly-Mycin), isolated in Japan, is a relatively new poly- myxin-like polypeptide antibiotic which is bacteri- cidal in vitro for species of Gram-negative bacilli
SOMMAIRE
Le colistiméthate de sodium (Coly-Mycine) a été employé pour traiter 17 malades: 13 cas d’infections des voies urinaires (deux d’entre eux avaient des hémocultures posi- tives), trois cas d’infections des voies respiratoires et un malade souffrait des deux formes d’infections. Chez neuf des 17 malades, un corps étranger, soit un cancer, soit une sonde, soit un calcul, venait compliquer l’infection.
La posologie appliquée a été de 1.1 à 2.3 mg./lb./jour, avec un maximum, dans un cas, de 2.4 g. donné pendant une période de huit jours.
Le germe pathogène comprenait du Pseudomonas dans six cas, l’Aerobacter dans six cas et de l’E. coli dans deux cas. Dans trois cas, on constatait la présence simultanée de Pseudomonas et d’Aerobacter.
Sur le plan bactériologique, six malades ont été guéris, huit ont eu des rechutes et, dans trois cas, l’agent infectieux fut remplacé par un autre germe pathogène. Les meilleurs résultats ont été obtenus chez les porteurs d’infection au Pseudomonas.
Parmi les réactions secondaires figuraient nausée, vomissement, paresthésies et douleur au point de piqûre.
Le colistimethate sodique a une place dans le traitement des infections dues aux germes à Gram-négatif, à l’exclusion des Proteus.
including E. coli, Aerobacter aerogenes and espe- cially Pseudomonas.1, 2, 4 It is not effective against Proteus.4, 5