ECTOPIC ADRENOCORTICOTROPIN SYNDROME ASSOCIATED WITH CARCINOMA OF THE COLON
ALAN BALSAM, M.D., GERALD BERNSTEIN, M.D., JAY GOLDMAN, M.D., BERNARD A. SACHS, M.D., AND HAROLD RIFKIN, M.D.
Department of Medicine, Montefiore Hospital and Medical Center, and the Albert Einstein College of Medicine, New York, New York
A 60-year-old man, with metastatic adenocarcinoma of the colon, presented with hypokalemic alkalosis, proximal myopathy, edema, glucose intolerance, and anemia. Elevated concentrations of plasma cortisol and radioimmunoassayable corticotropin (RIA-ACTH) and urinary 17-ketogenic steroids and 17-ketosteroids were not sup- pressed following the oral administration of dexamethasone, 8 mg per day for 2 days. The concentration of bioassayable ACTH in the colonic tumor was elevated, and a positive arteriovenous difference in radio- immunoassayable ACTH was demonstrated across the primary tumor. These data are interpreted as indicating that the tumor was the source of production and secretion of excessive ACTH and the resulting severe hyperadrenocorticism. The association of the ectopic ACTH syndrome with this nonchromaffin colonic neoplasm is ex- tremely rare.
Hyperadrenocorticism caused by ectopic production of adrenocorticotropin (ACTH) is associated with a number of different neoplasms. The large majority of cases involve tumors of the lung, pan- creas, and thymus.1, 2 Cancer of the gastrointestinal tract (esophagus,3 stom- ach, 4, 5 small intestine6), principally of the carcinoid variety, is rarely associated with ectopic ACTH production. The following case is an example of the ectopic ACTH syndrome associated with adenocarcinoma of the sigmoid colon, in which the tumor was demonstrated to contain and secrete ACTH.
Received August 6, 1971. Accepted November 8, 1971.
Address requests for reprints to: Dr. Alan Balsam, Department of the Air Force, USAF School of Aerospace Medicine (AFSC), Brooks Air Force Base, Texas 78235.
Dr. Balsam is a Major, USAF, MC, USAF School of Aerospace Medicine, Brooks AFB, Texas 78235.
The views expressed herein are those of the author and do not necessarily reflect the views of the United States Air Force or the Department of Defense.
Case Report
First admission. A 60-year-old pharmacist entered the hospital complaining of extreme weakness and ankle swelling. He had been in excellent health except for systolic hyper- tension which had been treated sporadically with antihypertensive agents for 5 years. Approximately 2 months prior to admission he developed a single episode of bright red rectal bleeding. Two weeks later he became anorectic, lost 5 lb in weight, noted pedal edema, and experienced difficulty in climbing stairs. Walking and arising from a sitting position became progressively more difficult because of muscle weakness. Two weeks before admission he ingested chlorthalidone 50 mg and reserpine 25 mg daily for 3 days. One week later his physician diagnosed severe proximal myopathy and noted marked glucose in- tolerance on an oral glucose tolerance test.
Physical examination revealed a middle-aged man whose severe weakness resulted in dif- ficulty in turning in bed, rising, and walking. Moon facies, hirsutism, central obesity, buffalo hump, striae, ecchymoses, and skin pig- mentation were not present. The blood pres- sure was 110/60 without postural change. Pertinent physical findings included: barrel-
shaped chest; harsh ejection murmur, grade III/VI, heard best along the left sternal border, radiating to the base and neck; liver palpable 2 fingerbreadths below the right costal margin, with hepatic dullness extending 10 cm; mod- erate bilateral pretibial and pedal edema; marked atrophy and weakness of the muscles of the shoulder and pelvic girdle; and hypo- reactive deep tendon reflexes. Rectal examina- tion revealed no masses, and the stool examina- tion for occult blood was positive. The re- mainder of the complete physical examina- tion was normal.
Laboratory findings. The following labora- tory studies were normal: leukocyte count and blood smear; urinalysis; prothrombin time; fasting blood sugar; serum bilirubin, globulin, cholesterol, uric acid, creatine phosphokinase, phosphorus; 24-hr urinary excretion of vanillyl- mandelic acid and 5-hydroxyindole acetic acid; intravenous pyelogram; motor nerve conduc- tion velocities and electromyography.
The following abnormal values were found: hematocrit 36%; platelets slightly decreased; blood urea nitrogen 34 mg per 100 ml; and serum sodium 136, potassium 1.7, carbon diox- ide 35.5, chloride 85 mEq per liter, alkaline phosphatase 170 mU per ml (normal range 30 to 85 mU per ml), lactic acid dehydrogenase 460 mU per ml (normal range 90 to 200 mU per ml), glutamic oxaloacetic transaminase 70 mU per ml, albumin 2.5 g per 100 ml, and calcium 8.1 mg per 100 ml. An oral glucose tolerance test showed blood sugar values as follows (milligrams per 100 ml): fasting, 110; 1/2 hr, 190; 1 hr, 225; 2 hr, 242; and 3 hr, 175.
The electrocardiogram was interpreted as regular sinus rhythm, rate 75, QT interval 0.40 sec and diffuse ST segment depression of 2 mm. A chest roentgenogram revealed left ventricular prominence. Bone marrow examina- tion disclosed stainable iron and was other- wise normal; serum haptoglobin was 355 mg per 100 ml, and the direct and indirect Coombs’ reactions were negative.
The patient was given 100 mEq of potassium chloride orally daily for 3 days and hypokalemia was incompletely corrected. Diagnostic testing was abruptly halted when the patient left the hosptial against the advice of his physician, 9 days after admission.
Second admission. He reappeared 6 days later because of the sudden onset of midepi- gastric distress and chest pain after eating. Paroxysmal atrial fibrillation with a ventricular response of 180 beats per min was noted and treated with potassium chloride and digoxin. A prompt return to regular sinus rhythm
occurred. Physical findings were unchanged except for the presence of an orange-sized, freely moveable, abdominal mass palpated in the left lower quadrant. Sigmoidoscopy to 25 cm disclosed bleeding from above but no discernible lesion. Barium enema showed a large polypoid lesion in the incisura of the sigmoid colon. The medial aspect of the right lobe and the entire left lobe of the liver were not visualized on scanning with technetium. An aortogram suggested neoplastic involve- ment of the liver and disclosed a tumor stain in the left lower quadrant. Adrenal venography was technically unsuccessful. Steroid and radioimmunoassayable (RIA)-ACTH measure- ments appear in table 1.
A polypoid lesion of the sigmoid colon (fig. 1A) was removed at surgery on the 11th hospital day. Arterial and venous heparinized blood samples for assay of RIA-ACTH were obtained at the tumor site, and the tumor was promptly frozen for later determination of bio- assayable ACTH activity (table 1). The liver was seeded with metastases. The left adrenal was removed and weighed 13 g; the right adrenal was matted under the liver and could not be mobilized. Histological examination re- vealed adenocarcinoma of the colon (fig. 1B) with replacement of local lymph nodes by tumor. Argentaffin staining of the tumor, em- ploying a positive control, showed no uptake of stain. There was no evidence of hyperplasia or tumor in the left adrenal gland. The post- operative course was characterized by pro- gressive hepatic failure, klebsiella sepsis, and thrombocytopenia. The patient died in his sleep 12 days after operation.
Postmortem examination revealed metastatic adenocarcinoma of the liver. The liver weighed 2710 g and was extensively replaced by tumor. Nine hundred milliliters of ascitic fluid were found in the abdomen. The colonic anastomosis was intact. The right adrenal weighed 6 g and showed no histological evidence of hyperplasia or tumor. A benign, 2-cm gastric ulcer was present in the midportion of the lesser curva- ture. Other pertinent findings included focal bronchopneumonia, a healed myocardial infarct in the intraventricular septum, and a benign laryngeal polyp. The pituitary gland appeared normal on gross examination. Microscopic examination following staining with hematoxylin and eosin revealed no changes. However, staining with aldehyde- thionine-periodic acid-Schiff-orange G (kindly performed and interpreted by Dr. C. Ezrin, University of Toronto School of Medicine) disclosed several 3-1 cells (which are presumed
| Date | Test | Plasma | Urine | Tumor | ||||
|---|---|---|---|---|---|---|---|---|
| Cortisolª | Radioimmunoassayable ACTH® | 17-ketogenic steroids | 17-keto- steroids | ACTH | ||||
| AM | PM | AM | PM | |||||
| ug/100 ml | pg/ml | mg/g creatinine/ 24 hr | mU/g | |||||
| (Normal range) | (5-25) | (5-25) | (<120) | (<120) | (5-23) | (9-22) | (0) | |
| 12/22/69 | Base line | 29 | 42 | |||||
| 12/26 | Base line | 43 | 54 | |||||
| 1/5/70 | Base line | 58 | 177 | |||||
| 1/6/70 | Dexamethasone (1 mg orally 11 PM night before) | 55 | 112 | |||||
| 1/7/70 | Base line | 64 | 67 | 130 | 166 | |||
| 1/8/70 | Base line | 70 | 62 | |||||
| 1/9/70 | Base line | 195 | 80 | 48 | ||||
| 1/12/70 | Dexamethasone (2 mg | 48 | 45 | 162 | 139 | 73 | 53 | |
| orally every 6 hr) | 169 | |||||||
| 1/13/70 | Dexamethasone (2 mg orally every 6 hr) | 46 | 50 | 169 | 156 | |||
| 1/15/70 | Tumor arterial blood | 157 | ||||||
| 1/15/70 | Tumor venous blood | 201 | ||||||
| 1/15/70 | Tumor ACTH | 0.05 | ||||||
” Performed by competitive protein-binding assay. 8
Kindly performed by Dr. D. N. Orth, Vanderbilt University School of Medicine.9
” Bioassays kindly performed by W. E. Nicholson, Vanderbilt University School of Medicine. 1º
to be the ACTH-producing cells) showing Crooke’s hyaline change.
Discussion
When this patient first entered the hospital, several features of his illness suggested the diagnosis of the ectopic ACTH syndrome. Hypokalemic alkalosis, proximal myopathy, edema, glucose intolerance, and anemia-characteristic findings of this syndrome-were present. Symptoms had been of short duration and the usual physical signs of Cushing’s syndrome were absent. Other diagnostic considerations such as adrenal tumor, Cushing’s disease, and villous adenoma, however, could not be rigorously excluded on the basis of the clinical findings and preliminary laboratory data.
Subsequently, the demonstration of markedly elevated, nonvarying concen- trations of plasma cortisol and increased excretion of 17-ketogenic steroids and 17-ketosteroids prompted further studies, using the radioimmunoassay of plasma ACTH and the more conventional plasma and urinary corticosteroid measurements
to define the etiology of the hyperadreno- corticism. The lack of suppression of plasma RIA-ACTH, plasma cortisol, and urinary glucocorticoid metabolites follow- ing the oral administration of high doses of dexamethasone (8 mg per day for 2 days) suggested that neither stress nor Cushing’s disease were likely explana- tions of the hyperadrenal state.1º More- over, the diagnosis of adrenal tumor was not tenable in the presence of consistently elevated concentrations of plasma RIA- ACTH. These data, together with the preoperative roentgenographic demon- stration of a sigmoid lesion, suggested that a colonic tumor might be a source of ectopic ACTH production, a suspicion later confirmed by direct assay.
Prior to laparotomy, it was decided to perform a bilateral adrenalectomy in order to halt the severe hyperadrenocorti- cism. This decision was based on the consideration that in the presence of metastatic disease, simple excision of the primary tumor might not eliminate excessive ACTH production. Ample preoperative evidence indicated the
A
presence of metastases: the liver was enlarged, liver function tests abnormal, and the liver scan and aortogram sug- gested hepatic involvement. At surgery, however, removal of the right adrenal gland proved technically not feasible. The patient’s condition deteriorated rapidly postoperatively, and death ensued in less than 1 month, 4 months after the onset of symptoms.
Bioassay of the colonic tumor revealed increased ACTH activity. The concen- tration of RIA-ACTH in the venous effluent of the primary tumor was approximately 30% greater than that of its arterial supply. The increased tumor concentration and the apparent positive arteriovenous difference of ACTH suggest that the tumor was a site of production and secretion of the hormone.
Until recently the association of the ectopic ACTH syndrome and cancer of the colon was largely unproven. In 1945, reporting on 17-ketosteroid measurements in patients with adrenal tumors, Warren described a case of a 38-year-old virilized female with a large abdominal tumor, whose 17-ketosteroid excretion measured 80 mg in 24 hr.11 Postmortem examination revealed a carcinoma of the splenic flexure with no evidence of adrenal tumor. This case, although suggestive of the ectopic ACTH syndrome, lacks clinical and biochemical data to establish a definite diagnosis.
Azzopardi and Williams12 reviewed the literature on the question of a causal relationship between carcinoma of the colon and “Cushing’s syndrome” and concluded that none was proved since 42, 13, 14 of the reported cases were accom- panied by adrenal adenomas.
The only documented case of the ectopic ACTH syndrome caused by carcinoma of the colon was reported by Miura et al. 15 in 1969. Their patient, a 52-year-old man, presented with uncontrolled diabetes mellitus, refractory hypokalemic alkalosis, melena, edema, pigmentation, and systolic hypertension. Endocrine evalua- tion disclosed elevated plasma cortisol, RIA-ACTH, urinary 17-hydroxycortico-
steroids and 17-ketosteroids. Thin layer chromatographic studies showed in- creased urinary excretion of etiochol- anolone. Plasma 11-hydroxycorticosteroids remained unchanged following the intra- venous administration of dexamethasone. Postmortem examination revealed metas- tatic adenocarcinoma of the ascending colon and bilateral adrenal hyperplasia. Histological examination of the primary tumor showed a small cell, anaplastic carcinoma compared with the moderately well differentiated adenocarcinoma ob- served in this case. Electron microscopic studies reavealed the presence of intra- plasmic secretory granules in the tumor cells, resembling serotonin granules. The serotonin content of the tumor and urinary excretion of 5-hydroxyindoles, however, were not increased. Radioimmunoassay and bioassay of ACTH demonstrated levels which were elevated in tumor tissue and depressed in the anterior pituitary.
Other ectopic humoral syndromes have been noted in association with adenocar- cinoma of the colon in rare instances. An insulin-like substance, or insulinoid, was demonstrated in the tumor of a patient with metastatic cecal cancer associated with hypoglycemia.16 Tumor extracts exhibited insulin-like activity in the rat diaphragm and adipose tissue assays but were immunologically distinct form insulin. In an additional case study, hypercalcemia was attributed to the secretion of para- thyroid hormone by colon cancer.17 Para- thyroid hormone activity was detected by complement fixation assay in both primary and metastatic tumor. At necropsy, four parathyroid glands of normal histological appearance were identified. Interestingly, no hormonal activity was detected in plasma in either of these 2 cases. In con- trast, in both this study and that reported by Miura, plasma levels of corticotropin were consistently elevated.
It appears quite evident that the radio- immunoassay of ACTH is a technique of considerable diagnostic importance. More widespread application of this assay in clinical medicine should permit rapid separation of the various etiologies of
hyperadrenocorticism and facilitate early detection and correct management of cases of the ectopic ACTH syndrome.
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