FULMINATING ADRENOCORTICAL HYPER- FUNCTION ASSOCIATED WITH ISLET-CELL CARCINOMA OF THE PANCREAS: CASE REPORT*
ALVIN A. ROSENBERG, M.D.
The Department of Medicine, All Souls Hospital, Morristown, N. J.
T HE association of adrenocortical hyperfunction and carcinoma of the pancreas is not coincidental and is of considerable interest. In a review (1) of 114 autopsies of patients with Cushing’s syndrome, the incidence of neoplasms other than those involving the adrenal or pituitary was reported as 10 per cent. There were 4 cases of pancreatic carcinoma.
Crooke (2) reviewed these 4 cases of pancreatic carcinoma associated with basophilism. In the first case an adrenal tumor was removed sur- gically, but it was a metastasis from a carcinoma of the head of the pan- creas that was found at autopsy. Full histologic details are not available. The second case was probably an acinar-cell carcinoma of the pancreas, although the authors believed that the tumor of the pancreas was derived from an adrenocortical rest because its cells contained granules which took an acidophil stain by Vines’ method; Crooke points out, however, that the zymogen granules of normal pancreatic cells also take this stain, and it is possible that this tumor was a primary pancreatic carcinoma. The third case was that of a 50-year-old woman with typical Cushing’s disease, but no detailed examination of the pancreatic tumor was reported. The fourth case was Crooke’s-a patient who had a scirrhous carcinoma of the pan- creas composed of abundant, dense collagenous tissue, embedded in which were cells which resembled in their staining the cells of the pancreatic acini.
Del Castillo et al. (3) in 1950 reported the first islet-cell carcinoma of the pancreas to be associated with Cushing’s syndrome. His patient was a 38- year-old Argentinian woman in whom a pancreatic lesion was suspected, but not proved before death, which occurred eight months after admission to the hospital. The case reported here is, therefore, the second in which an islet-cell carcinoma of the pancreas occurred in association with Cushing’s syndrome, and it is the first of the cases discussed in which an attempt was made to remove the pancreatic tumor at operation.
Received for publication February 8, 1956.
* This paper was presented at the Regional Meeting of the New Jersey Chapter of the American College of Physicians, Newark, N. J., November 9, 1955.
The most striking features about our patient and the 5 reported in the literature were: 1) that only 1 was as old as 50 years; among the other 5, 3 were between 20 and 30 years old, 1 was 38 and 1 was 40-ages at which carcinoma of the pancreas is rare; and 2) that in all, the disease was acute in onset and rapid in progress.
CASE REPORT
History
A 40-year-old white woman was admitted to All Souls Hospital, Morristown, N. J., on August 11, 1954, complaining of facial hirsutism and generalized swelling of three weeks’ duration. On July 22, 1954, because of headache and dysuria, she visited an osteopathic physician, who found generalized edema, and noted an occasional pus cell and some bacteria in her urine. He prescribed an antibiotic and ammonium chloride. A week later he gave her an injection of 2 milliliters of Mercuhydrin®, which resulted in a diuresis of about a gallon.
Pertinent facts on admission to the hospital were as follows:
Skin: Rounding of the face with puffiness of the eyelids and swelling of the legs had been recently noted. An excessive growth of fine hair had appeared on the upper lip and sides of the face within the previous three weeks. The skin had become oily and a few pustules had erupted on the face and chest. Easy bruisability and thinning of the skin were noted, and the nails had become brittle. About two weeks before admission, a black spot about 1 millimeter in diameter had developed on her right index finger. For five nights before admission sweating had been severe, but only from the waist up. A fungus infection about the anus had been present in early 1954, and had healed with great difficulty.
Central nervous system: Crying had recently been excessive. Sleepiness had been present for the previous three weeks and a throbbing headache for the previous two weeks.
Special senses: Everything tasted salty and there had been a craving for sweets.
Cardiovascular: There had been no dyspnea or orthopnea. The blood pressure was 128/78 mm. Hg on July 29, 1954 and 150/80 on August 10, 1954.
Gastro-intestinal: Appetite was greater than usual. Stools were watery and had recently averaged four per day.
Genito-urinary: Menses had been regular every twenty-six days until six months before, at which time a thirty-day cycle had become established with the exception of one seven-week interval. She had been pregnant twice, having 1 living 8-year-old child and 1 miscarriage. Nocturia had occurred twice in the period shortly before entry.
Musculo-skeletal: No muscular weakness had been noted. Aching in the lumbo-sacral region had been present for the previous three weeks, but such aching had been inter- mittently present since a back injury in 1942.
Physical examination
The patient was a well developed and nourished white woman, appearing about her stated age of 40 years (Fig. 1a). There was no dyspnea, orthopnea, or cyanosis. She did not appear acutely ill, but demonstrated moderate anxiety and depression. The temperature was 98º F., pulse 80, and respirations 16 per minute. Blood pressure was 148/80 mm. Hg.
Main findings were as follows: the face was ruddy and rounded with excessive fine hair on the upper lip and sides of the face (Fig. 1b). The axillary and pubic hair had a normal distribution. There were no striae. The skin otherwise was as described in the history. The retinal vessels showed slight A-V compression; the optic discs were not swollen or atrophic. The thyroid gland was symmetrical and slightly enlarged. Examina- tion of the heart, lungs, abdomen, pelvic organs, and genitalia revealed no significant abnormalities. There was 1+ edema of the legs. No muscular weakness was evident.
b. Marked hirsutism of the upper lip and face, slight rounding of the face and thickening of the neck.
Laboratory findings
Preoperative studies carried out at All Souls Hospital and Presbyterian Hospital are summarized in Table 1.
X-ray examinations
Skull and chest films were normal. Spinal studies indicated questionable deminerali- zation. In an intravenous pyelogram there was a suggestion of a dense area overlying the upper pole of the right kidney. Retrograde pyelography showed the same density. Presacral air studies then revealed a normal left kidney and adrenal gland; the right kidney shadow appeared normal, but there seemed to be a mass overlying the upper third of the right kidney; this was interpreted as a possible adrenal tumor.
| Procedure | Aug. 12, 1954-All Souls Hosp., Morristown | Aug. 29, 1954-Presbyterian Hosp., New York |
|---|---|---|
| Urine Culture | E. coli and Staphylococcus al- bus. No acid-fast bacilli. Neg- ative results with guinea-pig inoculation. | - |
| White Blood Count | 12,500 | 14,400 |
| Neutrophils | 84% | 96% |
| Lymphocytes | 16% | 4% |
| Eosinophil Count | 0 | - |
| Sedimentation Rate (Westergren) | 44 mm. in 1 hr. | - |
| Glucose Tolerance Test | Blood (mg./100 ml.) Urine | Blood |
| Fasting blood sugar ¿ hr. after 100 Gm. of glucose orally | 115 0 204 0 | 127 mg./100 ml. |
| 1 hr. after glucose | 224 0 269 2+ 279 4+ | |
| 2 hrs. after glucose | ||
| 3 hrs. after glucose | ||
| Total Plasma Proteins | 5.5 Gm. % 3.9 Gm. % | - |
| Albumin Globulin | ||
| 1.65 Gm.% 2.3:1 | ||
| A/G ratio | ||
| CO2 Capacity | 29.4 mEq./L | More than 34.7 mEq./L |
| Serum Sodium | 143.5 mEq./L | 148.5 mEq./L |
| Serum Chloride | 87.3 mEq./L | 81 mEq./L |
| Serum Potassium | 3.2 mEq./L | 1.8 mEq./L |
| Urinary 17-Ketosteroids | 37 mg. per 24 hrs. (Norumbur- ski method; normal 5-15 mg. in 24 hrs.) | 39-47 mg. per 24 hrs .; no de- crease following i.v. hydrocor- tisone |
| Plasma Corticoids | - | 92 gamma per 100 ml. (Wallace & Christy method; normal 4-32 gamma per 100 ml.) |
| Urinary Corticoids | - | 41-48 mg. per 24 hrs. (Porter- Silber method; normal 2-6 mg. in 24 hrs.) |
| Electrocardiogram | Normal | Left ventricular hypertrophy, or digitalis effect, or both |
The following determinations yielded results within the normal range: red blood cell count and hemoglobin, urinalysis, serum calcium and phosphorus, blood urea nitrogen, alkaline phosphatase, cephalin flocculation, and basal metabolic rate.
Course
The patient spent ten days at All Souls Hospital while investigations were proceeding. She had spells of weeping and depression during the latter part of her stay. The edema subsided when she received a salt-free diet. There was a reduction in weight from 125
pounds on admission to 119 pounds on discharge. Another small black spot developed on the right third finger while she was under observation.
The patient was discharged from All Souls Hospital on August 20, 1954. On August 29, 1954 she was admitted to the service of Dr. George F. Cahill at the Presbyterian Hospital in New York City.
Dr. Cahill thought the patient had acute Cushing’s syndrome, and that the labora- tory evidence favored adrenal carcinoma.
She was given a regular diet and continued to have 3+ to 4+ sugar in the urine. No insulin was added. On September 6 she became psychotic and had suicidal tendencies. Her weight increased from 115 pounds on August 29 to 125 pounds on September 12. She was given an injection of Mercuhydrin® and 200 milligrams of cortisone on Sep- tember 12. There was a loss of 18 pounds by the next day.
Operation
On September 13, through a transverse abdominal incision, Dr. Cahill unexpectedly discovered and removed an orange-sized tumor from the midportion of the pancreas. Both adrenals felt normal at operation. No surface metastases were seen on the liver, but irregular, firm areas were felt.
Postoperative period
Postoperatively cortisone and desoxycorticosterone were continued in gradually decreasing doses; maintenance doses of streptomycin, penicillin, and digitoxin were also administered. On the first postoperative day her temperature rose to 104º F., falling a little on succeeding days. Her abdomen became distended and bowel sounds were hypo- active. By the fourth postoperative day she was disoriented. Severe hypotension de- veloped and she lapsed into coma. Hydrocortisone and noradrenaline were infused, but the temperature rose to 105° F. in spite of apparently clear lungs and the absence of localizing signs. The patient died on the fifth postoperative day (September 18, 1954), approximately two months from the time she perceived the first symptoms.
Postoperative laboratory findings are summarized in Table 2.
Autopsy report
Unfortunately, permission for examination of the pituitary and brain could not be obtained and the autopsy was performed entirely through the abdominal incisional wound by Dr. D. Benninghoff, Presbyterian Hospital, New York. The main findings were as follows:
Pancreas: On exploring the pancreas in situ, about 20 ml. of necrotic material exuded from the site of the body of the pancreas, which appeared to have been surgically excised. The head and tail of the pancreas were intact, yellowish-brown in color, and firm in consistency with no evidence of tumor. At the site of the excised tissue there was considerable reddening and inflammation; there were fibrinous adhesions to the pancrea- tic surface of the stomach in that location.
Microscopic examination (Fig. 2) revealed pancreatic tissue, portions of which had been replaced by atypical cells arranged in nests and cords surrounded by dense con- nective tissue septa and resembling islet cells. The individual cells possessed irregular round or oval vesicular nuclei; the cytoplasm was acidophilic, granular, and sparse; the cell membranes were indistinct. Numerous vacuole formations were observed.
In some areas fibrosis and hyalinization had occurred, and the tumor cells were seen
TABLE 2. POSTOPERATIVE LABORATORY FINDINGS
.
| Procedure | Days after operation | ||
|---|---|---|---|
| 0 | 3 | 4 | |
| Serum Sodium | 142.0 mEq./L | 135.0 mEq./L. | 147.0 mEq./L |
| Serum Potassium | 1.8 mEq./L | 2.5 mEq./L | 3.6 mEq./L |
| Serum Chloride | - | 84.0 mEq./L | 96.0 mEq./L |
| CO2 Capacity | - | More than 34.7 mEq./L | 18.0 mEq./L |
| Blood Sugar | - | 434.0 mg./100 ml. | - |
| Electrocardiogram | - | Suggestion of hypokaliemia | - |
to surround blood vessels and nerve bundles. Other foci showed infiltration by strands and cords of atypical cells which were more undifferentiated. These anaplastic cells had small spindle-shaped, hyperchromatic nuclei. Mitotic figures were moderate in number.
Adrenals: The left adrenal weighed 16.5 grams and the right 21.0 grams. Although these organs were grossly enlarged, the cortical zone did not appear to be significantly increased in size. There was no gross evidence of localized lesions in the adrenal glands and on cut section the golden-yellow brown cortex was well demarcated from the whitish medulla. Examination of the left adrenal was not completely satisfactory because considerable autolysis and maceration had taken place in removing it.
Microscopic examination revealed hyperplasia of the cortical elements of both
adrenals, the zona fasciculata being particularly prominent; numberous foam cells were noted. No tumor was present.
Liver: The liver was enlarged, extending S centimeters below the costal margin and weighing 1,600 grams. On its surface there were several small whitish nodular areas surrounded by a zone of purplish discoloration. On palpation, these areas were very firm in consistency. On cut section the liver was found to have several of these greyish-white nodules throughout its parenchyma, the largest measuring 5.5 centimeters in diameter. Most of the other nodules were 5-10 millimeters in diameter. The remainder of the liver was pale tan in color and firm in consistency.
Microscopic examination revealed moderate fatty metamorphosis, largely centrilobu- lar in location, along with focal central necrosis and a considerable amount of glycogen vacuolization of the hepatic cells. Tumor was present in two of the sections and its cells were arranged as masses of anastomosing cords. Nuclei were for the most part large, hyperchromatic, and ovoid or spheroid in shape; their cytoplasm was eosinophilic and the tumor cells resembled those of the islets of Langerhans.
Heart: This organ weighed 275 grams and was unremarkable grossly and micro- scopically.
Aorta: Scanty atheromatous changes were present in the portion of abdominal aorta examined.
Lungs: The lungs were crepitant throughout. Congestion of the septal vessels and foci of atelectasis were evident. There were red cells and macrophages containing yellow- brown pigment in the alveoli.
Pathologic diagnosis
1. Islet-cell carcinoma of the body of the pancreas with metastases to the liver.
2. Bilateral adrenal hyperplasia.
3. Postoperative acute pancreatitis.
COMMENT
Evidence for the conclusion that the patient was suffering from an ad- renal carcinoma was the shadow overlying the right kidney, observed in all x-ray studies, and the failure of the urinary 17-ketosteroid level to fall after the administration of intravenous hydrocortisone. The mass seen on x-ray examination remained unexplained, both at operation and at au- topsy. Cahill (4) has stated that the interpretation of perirenal air insuf- flation films of patients with Cushing’s syndrome is particularly difficult because of the “edema in the perirenal tissue” in this condition.
Since adrenal hyperfunction was obviously present and an adrenal lesion suspected, an attempt was made to determine whether it was benign hyperplasia or a tumor, by means of the intravenous hydrocortisone test as proposed by Jailer (5). The test results were considered negative, in- dicating the presence of a tumor which was autonomous in behavior and situated either in the pituitary or the adrenal gland. That it was not in the adrenal was proved at laparotomy. Whether or not it was in the pituitary unfortunately could not be investigated because of the restrictions imposed
on the autopsy. However, if one considers this test valid, the conclusion is that the patient was suffering from a pituitary tumor which induced the adrenal hyperplasia.
The patient’s symptoms and signs differed from those usually associated with Cushing’s disease, in that she was not obese, there were no striae, the blood pressure and red blood count were normal, and menstruation had continued more or less regularly. In all other respects the preoperative laboratory findings were in accord with those usually observed in adreno- cortical hyperfunction or following prolonged treatment with cortico- tropin or cortisone. Characteristic of this condition were the leukocytosis with lymphopenia and absence of eosinophils, the diabetic-type glucose tolerance curve, decreased level of plasma proteins, hypochloremic alkalo- sis, low level of serum potassium, increased urinary 17-ketosteroids, and increased plasma and urinary corticoids. An elevated sedimentation rate has not been described in adrenocortical hyperfunction; the elevated rate in our case may have been due to the pancreatic carcinoma. The differ- ences noted between our findings and those in Cushing’s syndrome may well have been due to the accelerated course of the disease in this patient.
Neither in this case nor in del Castillo’s (3) was there a history of hypoglycemic attacks; both patients, in fact, had a glucose tolerance curve of the diabetic type. This is not surprising, however, since only a minority of islet-cell tumors are functional. Melicow (6) reviewed the autopsy re- cords of 4 patients with islet-cell tumors of the pancreas, and in none was there any significant finding in the adrenals.
The postoperative course, metabolically, was characterized mainly by the persistent hypopotassemia, hyperglycemia and hypochloremic alkalo- sis. It is interesting, but unexplained, that the carbon dioxide capacity dropped from more than 34.7 mEq./L to 18 mEq./L within the twenty- four hours preceding death. It was felt that the acute pancreatitis around the area of excision was probably sufficient to tip the balance in this case, since patients with Cushing’s syndrome are known to tolerate postopera- tive inflammation or infection very poorly. Moreover, this patient was treated with gradually decreasing doses of cortisone and desoxycortico- sterone postoperatively. This would tend to enhance the already existent adrenocortical hyperfunction, since the adrenals were not excised at opera- tion and a test dose of intravenous hydrocortisone had caused no decrease in production of 17-ketosteroids. Thus it was indicated that any cortisone administered to this patient would augment the endogenous supply rather than decrease its production in the normal manner.
When Cushing’s syndrome is associated with a tumor, there is always the question of whether the neoplasm causes the hyperadrenalism or
whether the latter causes or encourages the growth of the neoplasm. M. G. Thorne (7) and others have discussed the various relationships but as yet there is no definite answer. Thorne concludes “it is possible that the aetiological relationship is more subtle; that an innate abnormality of adrenal cortical metabolism destined in later life to give rise to malignant. disease, is precociously awakened in Cushing’s syndrome, possibly as a result of excessive production of adrenocorticotrophic hormone. This would be compatible with the fact that the neoplasms here discussed occurred chiefly in young subjects and with the conception, previously expressed by Findley (1949), that Cushing’s syndrome affords a ‘possible clue to cer- tain disorders associated with ageing’.”
In only 1 other instance was an attempt made to remove the tumor-a thymic carcinoma, in a patient reported by Hubble (8). In this patient death occurred twenty-four hours after operation, too soon to determine what effect such removal would have on the hyperadrenalism. In our case, death occurred five days after operation-also too soon to determine the effect of removal of an islet-cell carcinoma of the pancreas on the symp- toms of hyperadrenalism.
SUMMARY
1. The second case of hyperadrenocorticism (Cushing’s syndrome) associated with islet-cell carcinoma of the pancreas has been presented.
2. Five cases of Cushing’s syndrome associated with carcinoma of the pancreas have been previously reported. This sixth case of adrenocortical hyperfunction is the only one in which an attempt was made to remove the pancreatic tumor.
3. The use of the intravenous hydrocortisone test in the differential diagnosis of adrenal hyperplasia and pituitary or adrenal tumor is dis- cussed.
4. The possible relationship of adrenal hyperplasia to carcinogenesis is noted.
Acknowledgments
The author wishes to thank Dr. D. Benninghoff for the autopsy report, Dr. M. M. Melicow for the report on the pancreatic tumor removed at operation, and Dr. George F. Cahill for the report on the patient’s course while at the Presbyterian Hospital in New York.
He also wishes to express his appreciation to Miss Dolores Breen of the Jersey City Medical Center for the photographs, and to Mr. Morton Pollack of Morristown, N. J. for the photomicrographic reproduction.
REFERENCES
1. PLOTZ, C. M .; KNOWLTON, A. I., and RAGAN, C .: The natural history of Cushing’s syndrome, Am. J. Med. 13: 597 (Nov.) 1952.
October, 1956 ADRENOCORTICAL HYPERFUNCTION & ISLET-CELL CA. 1373
2. CROOKE, A. C .: Basophilism and carcinoma of the pancreas, J. Path. & Bact. 58: 667 (Oct.) 1946.
3. DEL CASTILLO, E. B .; TRUCCO, E., and MANZUOLI, J .: Maladie de Cushing et cancer du pancréas, Presse méd. 58: 783 (July 5) 1950.
4. CAHILL, G. F .; MELICOW, M. M., and DARBY, H. H .: Adrenal cortical tumors: the types of nonhormonal and hormonal tumors, Surg., Gynec. & Obst. 74: 281 (Feb.) (No. 2A) 1942.
5. JAILER, J. W .: Hormones in Health and Disease, ed. 1. New York, The Macmillan Co., 1954, pp. 158-160.
6. MELICOW, M. M .: Personal communication to the author.
7. THORNE, M. G .: Cushing’s syndrome associated with bronchial carcinoma; enquiry into relationship of this syndrome to neoplastic disease, Guy’s Hosp. Rep. 101: 251, 1952.
8. HUBBLE, D .: Cited by Plotz et al. (reference 1).