ADRENAL CORTICAL CARCINOMA ASSOCIATED WITH HYPOGLYCAEMIA”
C. L. ASZKANAZY, M.D., L. JENKINS, M.D. and W. W. SIMPSON, M.D., Vancouver, B.C.
IN RECENT YEARS there have been several reports of patients with large tumours in the upper abdomen or lower chest, in whom the main symptom and sometimes the cause of death was a marked hypo- glycæmia.1-11, 13-15 The direct causal relationship of the neoplasm to the low blood sugar level was indicated in some instances by the disappearance of the hypoglycemia after resection of the tumour3, 6, 9, 10, 15 and its recurrence with regrowth.“ Skillern et al.14 believed that such lesions were of ectopic islet cell origin. Yet insulin assays, al- though only rarely carried out on these tumours, were negative in at least two previous instances.10, 11 In the case to be described here, not only was insulin absent from the main tumour and its metastases but the pancreas also had only a normal insulin content, so that the fortuitous presence of a small functioning islet cell adenoma could be excluded.
Clinical summary .- A 26-year-old woman developed attacks of low back pain, followed within a few months by enlargement of the abdomen and episodes of epi- gastric discomfort. One and a half years later she con- sulted a doctor for increasing weakness. A low blood sugar level was found and a high carbohydrate diet prescribed. After a further six months she went to bed with an attack of especially severe back pain and marked distension of the abdomen. Within two days she became irrational, then lapsed into coma and was admitted to hospital.
The patient was pale and had a cool moist skin, pulse rate 110, blood pressure 130/70 mm. Hg, respir- ations 18. The reflexes were hyperactive and there was prolonged ankle clonus, but the plantar responses were absent. The extremities were rigid and extended with a bilateral carpopedal spasm. A large mass was pal- pable in the left upper quadrant of the abdomen, ex- tending to 4 cm. below the left costal margin.
The blood sugar was 37 mg. %. Urine, hæmoglobin level, white blood cell count, sedimentation rate, serum amylase, non-protein nitrogen (N.P.N.), serum electro- lytes, serum calcium, liver function and the spinal fluid were all normal. An electrocardiogram showed sinus tachycardia at 110 per minute; an electroence- phalogram was diffusely abnormal from a deep mid- line origin (blood sugar level at that time was 96 mg. %). Radiographs of the chest, skull and lumbo- sacral vertebræ were normal. A barium meal revealed an extrinsic retroperitoneal mass. An intravenous pye- logram was normal, but the left kidney was depressed and rotated.
After intravenous glucose administration the patient became conscious, but the blood sugar could be main- tained at normal levels only by constant oral or intravenous glucose therapy.
A laparotomy was undertaken to determine the nature of the abdominal mass. A large tumour was found at the upper pole of the left kidney, and metastases were noted in the liver. The pancreas lay in front of the tumour but appeared normal. Biopsies from the main mass and a liver metastasis showed an anaplastic carcinoma. In Gömöri stains some of the cells were thought to contain a few indefinite blue granules, and partly on this basis, but more so because of the clinical history, a functioning islet cell carcinoma was diagnosed.
During the next weeks the maintenance of adequate blood sugar levels proved increasingly difficult. Hypo- glycæmic episodes became frequent, and between attacks the blood sugar remained fixed at 30-50 mg. %. The patient died about one month after hospitalization during an attack in which no blood sugar was demon- strable.
POSTMORTEM EXAMINATION
Gross findings .- The body was that of a somewhat obese young woman. The abdomen was protuberant and contained marked lower abdominal striæ and a recent laparotomy scar. Slightly excessive hair was present on the upper lip and chin, but otherwise the female sex characteristics were quite normal.
The main lesion was found in the upper abdomen and consisted of a very large globular tumour mass, measuring 18 cm. in diameter and weighing 2200 g., which had replaced the left adrenal gland (Fig. 1). The tumour on section was somewhat lobulated, fleshy, soft and white, with a large yellow necrotic centre. It had depressed and indented the left kidney and had displaced the aorta and inferior vena cava to the right of the vertebral column. The body and tail of the pancreas were flattened and lay across the front of the tumour but despite some adhesions could be freed by blunt dissection. Worms of putty-like material could be squeezed from the tail of the pancreas in the area of the previous biopsy. Although the tumour was mostly encapsulated, it had penetrated the capsule at the superior pole, invaded the left leaf of the diaphragm and had seeded metastatic nodules on its pleural surface. The left pleural cavity contained 500 c.c. of clear straw-coloured fluid.
The tumour filled the left renal vein and extended from there into the inferior vena cava, which was
*From the Departments of Pathology and Medicine, Univer- sity of British Columbia and Vancouver General Hospital.
completely blocked, up to about 1 cm. from the liver. The tributaries of the caval vein below the block were engorged, and especially the pelvic veins were markedly tortuous and partly thrombosed. Both lungs and the liver were studded with metastatic nodules measuring 1 to 6 cm. in diameter. The lymph nodes were uninvolved. The lungs were œdematous and con- tained small emboli and infarcts.
The other organs, including the right adrenal gland, were grossly normal, although all tended to be excessive in weight.
Microscopical findings .- The tumour in the primary area and metastatic deposits showed identical histo- logical features. It consisted of sheets of fairly large polygonal cells with eosinophilic or vacuolated cyto- plasm and round or oval nuclei (Fig. 2). Occasional giant cells with very large hyperchromatic nuclei were present and mitotic figures were abundant. Fat could be demonstrated in the vacuolated neoplastic cells in frozen sections stained by Sudan III. Gömöri stains of the tumour material were uniformly negative, while satisfactory staining of the beta cells in the islets was obtained by similarly treating sections of the pancreas. Areas of necrosis were scattered through the tumour. The blood supply was abundant and con- sisted of many thinwalled and sinusoidal vessels.
Several blocks taken from the pancreas showed only normal acinar and islet tissue. In the region of the previous biopsy, fat necrosis, foreign body giant cells and granulation tissue were present.
In the liver and spleen there were small foci of extramedullary hæmopoiesis, and a few megakaryo- cytes were lodged in the sinusoids. Bone marrow from a lumbar vertebra was normal. Although one cannot exclude the possibility that the extramedullary hæmo- poiesis was associated with metastases to bone, there was no radiological evidence for this assumption. Since adrenal cortical hormones stimulate the bone marrow to overproduction of cells,17 hormonal activity of the tumour may have been responsible for the blood formation in liver and spleen.
Sections of the liver stained for glycogen were negative.
The lungs contained small organizing infarcts.
In the brain, some of the larger nerve cells in the cerebral cortex were shrunken, eosinophilic and devoid of Nissl substance, a change compatible with anoxia or hypoglycæmia.
The other organs, including the pituitary gland and right adrenal, were histologically normal. The breasts
and female genitalia showed the physiological activity appropriate for a young woman.
Pathological diagnoses. - Carcinoma of the left adrenal cortex; tumour invasion of diaphragm, left renal vein and inferior vena cava; metastases to liver and lungs; left hydrothorax; pulmonary œdema; hypo- glycæmic nerve cell changes in brain; pulmonary emboli and infarcts; extramedullary hæmopoiesis of liver and spleen; fat necrosis and foreign body granu- loma of tail of pancreas; macrosplanchnia.
Insulin assay (Dr. G. A. Wrenshall) .- Portions of the main tumour mass, metastases to the lung and liver, the right adrenal gland and the entire pancreas except for the blocks examined microscopically were assayed for insulin. All specimens of tumour and the right adrenal gland were negative for insulin, while the pancreas contained approximately 1 unit per gram, a low normal value.
COMMENT
To date no satisfactory explanation exists for the hypoglycæmia associated with non-pancreatic tumours. The contention of Skillern et al.14 that these lesions are of ectopic pancreatic origin is hardly tenable in view of the histological diversity among the neoplasms reported. Five,1, 4, 7, 15 includ- ing our own, were interpreted as carcinomas of the adrenal cortex and in three the diagnosis was supported by a raised urinary output of 17-keto- steroids. A sixth case was of a large adrenal cortical adenoma.º There were further two fibromas,11, 13 four fibrosarcomas,3, 5, 10 one retroperitoneal sar- coma,2 one liposarcoma6 and two cases of pseudo- myxoma peritonei.“
The suggestion that such tumours elaborate an insulin-like substance1 has recently received support by August and Hiatt,3 who were able by means of the Vallance-Owen test to demonstrate in their case of a pleural fibrosarcoma the presence of an agent which promoted the uptake of glucose by the isolated rat diaphragm. On the other hand, insulin assays on other tumours,10, 11 including our own, were negative. Hines6 has suggested that some metabolic product of the tumour stimulates the pancreas to a greater output of insulin. Alterna- tively he has suggested that a release from the tumour of some substance requiring excessive car- bohydrate for its metabolism might have occurred, or that a similar demand by the rapidly proliferat- ing neoplastic cells might exist. Our data shed no new light on these possibilities.
It is tempting to postulate a hormonal disturb- ance of the control of the blood sugar level in patients with an adrenal neoplasm.4 Although in- creased activity of the adrenal cortex usually leads to hyperglycæmia, children with an overgrowth of the androgenic zone may exhibit the Addisonian syndrome with a low blood sugar level.16 Selye12 found that rats given desoxycorticosterone acetate and then exposed to stress developed a marked hypoglycæmia, thus proving that excess of one adrenocortical hormone can suppress the action of another one.
Finally, Lawrence7 and Seckel11 suggested that these tumours, by virtue of their location and large size, stretch the sympathetic nerve trunks or re- ceptors in the liver, adrenals and pancreas and thus interfere with glycogen mobilization. This theory is perhaps the most plausible one since it takes into account the features common to all the tum- ours and is thus applicable to the whole group.
SUMMARY
A case is reported of a large adrenal cortical car- cinoma in a young woman, associated with severe hypoglycemia which led to the death of the patient. The literature on similar cases and current theories on the pathogenesis of the hypoglycemia are briefly dis- cussed.
We are indebted to Dr. G. A. Wrenshall, Banting and Best Department of Medical Research, University of Toronto, for the insulin determinations.
REFERENCES
1. ANDERSON. H. B .: Am. J. M. Sc., 180: 71, 1930.
2. ARKLESS, H. A .: M. Bull. Vet. Admin., 19: 225. 1942.
3. AUGUST. J. T. AND HIATT, H. H. : New England J. Med., 258: 17. 1958.
4. BROSTER, L. R. AND PATTERSON, J .: Brit. M. J., 1: 781, 1948.
5. DOEGE, K. W .: Ann. Surg., 92: 955, 1930.
6. HINES, R. E .: M. Bull. Vet. Admin., 20: 102, 1943.
7. LAWRENCE, C. H .: Ann. Int. Med .. 11: 936. 1937.
8. ROSENFELD, E. D .: Arch. Path., 48: 255. 1949.
9. SCHAMAUN. M., DEUCHER. F. AND GABLINGER, S. : Schweiz. med. Wohnschr., 87: 1348, 1957.
10. SCHOLZ, D. A., WOOLNER. L. B. AND PRIESTLEY, J. T. : Ann. Int. Med., 46: 796, 1957.
11. SECKEL, H. P. G. : J. Clin. Invest., 18: 723, 1939.
12. SELYE, H. AND DOSNE, C .: Endocrinology, 30: 581, 1942.
13. SILVIS, R. S. AND SIMON, D. S. : New England J. Med., 254: 14, 1956.
14. SKILLERN, P. G., JR. et al .: Diabetes. 3: 133. 1954.
15. STAFFIERI, J. J., CAMES, O. AND CID, J. M .: J. Clin. Endocrinol., 9: 255, 1949.
16. WILKINS, L., FLEISCHMANN, W. AND HOWARD, J. E. : Endocrinology. 26: 385, 1940.
17. WINTROBE, M. M .: Clinical hematology, 4th ed., Lea & Febiger, Philadelphia, 1956, pp. 45, 223, 796.
Special Article
MAN, MACHINES AND EMOTIONS*
STANLEY GREENHILL, M.D., Edmonton
EVER SINCE MAN gave up the security of the tree tops, and the advantages of prehensile toes and a tail, he would appear to have been plagued with feelings of insecurity. Man, by his actions, gives the impression that he has never really adjusted to the uncertainty of life at ground level. From pre- historic times his unique ability to think has been concentrated on devising ways and means of over- coming his physical shortcomings, and removing threats, real or imagined, that make life on terra firma a somewhat hazardous business.
Being but human, Man has shown a consistent propensity for misapplying his ever increasing
technical skills. He now possesses the skill to obliterate not only himself, but also all he has ever achieved. This is naturally a matter for some concern. Though man has progressed from the sharpened flint to “the ultimate deterrent”, it must also be remembered that the abacus has been re- placed by UNIVAC, the ox-drawn cart by the jet transport, the witch’s brew by modern medica- tions, and even psychiatry can be regarded as an advance on the oracle or the more bloodthirsty of exorcistic rituals. The maintenance of a state of balance and proportion is essential, lest contempla- tion of man’s more spectacular technical skills produce a state of petrified pessimism. To counter- balance this gloom and despondency, it seems advisable to look at some new production tech- niques-techniques that may remove much of the drudgery from human life, and allow man the time and opportunity to devote himself to worth- while and constructive pursuits.
MECHANIZATION v. AUTOMATION
In the past 50 years or so significant changes have occurred in the approach to the problem of mechanical aids and production techniques. No longer is the problem merely that of devising more efficient means of placing more horsepower at the disposal of the individual worker. The problem now is to find methods whereby more and more goods can be produced by fewer and fewer men. Until now the “assembly line” has been regarded as the ultimate in the mass production of goods. The idea of bringing constituent parts to workers instead of workers taking the parts to an assembly site was regarded as revolutionary as well as im- practical. It required a Henry Ford to prove that the idea was not only practical but also of con- siderable economic worth.
Assembly-line production was undoubtedly a great advance. Goods of great complexity could be produced in great numbers at reasonable prices. Productivity per worker reached undreamt of heights. But the method contained one glaring imperfection. Its success depended on its human component-a component that has always been famous for its inability to comply with rigid specifications plus its susceptibility to breakdown. The exclusion of such an unreliable bit of equip- ment from any production system would obviously be a great technological achievement.
AUTOMATION
How could this dream be realized? As usual, it took a war to provide the motivation, funds, and brainpower. Guns had to be made to fire with accuracy at distant fast-moving targets. Human brain and brawn were too slow for such a job. The computer-aimed-and-fired weapon came into being. At long last inanimate machinery evidenced some purposeful action without human interfer- ence. If such techniques could be applied to engines of war, they obviously could be applied to the less stringent demands of peace.
This technique of machines supervising other machines and continuously producing finished goods without humans playing the time-honoured role of “workers” is the essence of automation.
*Based on an address given at a two-day seminar on mental health in industry, sponsored by the Canadian Mental Health Association, Calgary, March 1958.