PEARLMAN, A. (1940), “Amyloidosis, A Clinical and Pathological Study of 135 Cases”, Quart. Bull. Sea View Hosp., 6 : 295.
PEARLMAN, A. (1940), “Regression of Amyloidosis”, Quart. Bull. Sea View Hosp., 6 : 92.
REIMANN, H., KOUCKY, R., and EKLUND, C. (1935), “Primary Amyloidosis, Limited to Tissue of Mesodermal Origin”, Am. J. Path., 11 : 977.
STEMMERMAN, M. G., and AUERBACH, O. (1944), “Adrenal Amyloidosis”, Arch. Int. Med., 74 : 384.
TRASSOFF, A., SCHNEEBERG, N., and SCARF, M. (1944), “Recovery from Multiple Rheumatoid Arthritis Complicated by Amyloidosis in a Child”, Arch. Int. Med., 74 : 4.
TRUBOWITZ, S. (1950), “The Sternal Marrow Aspiration of Amyloid in Multiple Myeloma”, Blood, 5 : 581.
WILD, C. (1886), “Beitrag zur Kenntnis der amyloiden und der hyalinen Degenerations des Bindegewebes”, Beitr. 2. path. Anat. u. Physiol., 1:177.
Legends to Illustrations.
FIGURE I .- Medial infiltration of a pulmonary vessel with narrowing of the lumen
FIGURE II .- A nodular amyloid deposit within the myo- cardium.
FIGURE III .- Diffuse amyloidosis of the lung.
FUNCTIONAL ADRENAL CORTICAL CARCINOMA COMPLICATED BY A PERFORATED GASTRIC ULCER: REPORT OF A CASE WITH POST-MORTEM FINDINGS.
- By C. H. CAMPBELL, M.B., B.S., Junior Resident Pathologist, Kanematsu Memorial Institute of Pathology, Sydney Hospital.
Ir has become apparent that peptic ulceration is one of the complications which may arise during treatment with some of the adrenal gluco-corticoid hormones or ACTH. It is of some interest, therefore, to report a case of an adrenal cortical carcinoma which was complicated by a peptic ulcer, particularly as there was evidence of the production of a gluco-corticoid-like hormone by the tumour.
Kepler et alii (1948) have reported a case in which these two conditions were present, but they were not thought to be related.
Clinical Record.
E.A., a female patient, aged seventy-two years, was admitted to the Eye Department of Sydney Hospital on August 14, 1952, with a cataract in the left eye. On account of her general condition she was discharged and referred to the general outdoor department for investigation. On August 23 she was admitted to the gynæcological ward with a provisional diagnosis of carcinoma of the body of the uterus, diabetes mellitus and hypertensive congestive cardiac failure.
When questioned about her illness, she said that she had “no complaints”; further interrogation brought the following symptoms to light: vaginal bleeding of three months’ duration (necessitating the use of three pads per day), increasing breathlessness on exertion for ten years, so that now she became breathless on walking a few steps, swelling of the ankles of one month’s duration, and “an indigestion pain” of doubtful duration. Her menstrual history had been normal up to the menopause at the age of forty-six years. There had been no vaginal bleeding since then until this illness. She had had one miscarriage and eleven children, all born normally.
The patient was a short, obese, plethoric woman. Her pulse rate was 90 per minute and the pulse was regular in time and amplitude. The heart was enlarged on clinical examination. The heart sounds were normal. The blood pressure was 160 millimetres of mercury, systolic, and 110 millimetres, diastolic. There was gross pitting œdema of the whole of the lower limbs. The respirations numbered 22 per minute. The percussion note was dull and there were crepitations at the bases of both lungs. The abdomen was swollen and obese, and there was doubtful ascites.
The external genitals were normal. On vaginal examina- tion, the cervix had a ragged nobbly anterior lip, the uterus was retroverted and slightly enlarged. The specific gravity of the urine was 1018. There was a ”+” reaction for albumin, ”+++” for sugar and ”++” for acetone.
A number of investigations were carried out, with the following results. The hæmoglobin value was 14.2 grammes per centum; the blood urea nitrogen content was 12 milli- grammes per 100 millilitres of blood; the blood creatinine content was 1.5 milligrammes per 100 millilitres of blood; the standard urea clearance was 78% ; the blood sugar content was 129 milligrammes per 100 millilitres in the fasting state, 195 milligrammes per 100 millilitres half an hour after the ingestion of 50 grammes of glucose, and 221 milligrammes per 100 millilitres two hours after the ingestion of 50 grammes of glucose. X-ray examination of the chest showed an increase in the transverse diameter of the heart and congestive changes in the lung fields. The urinary 17-ketosteroid estimation was 11.8 milligrammes per twenty-four hours specimen.
The patient was subsequently transferred to the care of a physician and received a 1700 Calorie salt-free diabetic diet, “Digoxin” (0.25 milligramme) and aminophylline (100 milligrammes) three times a day, injections of ordinary insulin, 15 units at 7.30 a.m. and 12 noon, and 10 units at 4.30 p.m., and intramuscular injections of “Thiomerin”, two mils per day, twice a week. The glyco- suria was controlled up till a few days before her death. There was no response to the mercurial diuretic. No alteration in her clinical condition occurred until Sep- tember 12, when suddenly at 6 a.m. the patient had a severe epigastric pain. When she was examined the pulse rate was 80 per minute, and the pulse was regular in time and amplitude. The heart sounds were normal. The blood pressure was 150 millimetres of mercury, systolic, and 80 millimetres, diastolic. There was some tenderness in the epigastrium, but no guarding. The patient was afebrile and there was slight glycosuria. At 8 a.m. the pain was still severe. She vomited five ounces of thick, viscid, bile- stained fluid. Her abdomen now was distended and resonant, and the blood pressure had dropped to 90 milli- metres of mercury, systolic, and 70 millimetres, diastolic. A provisional diagnosis of acute myocardial infarction was made. Later, hæmorrhage began per vaginam, and she became very dyspnœic and cyanosed and died at 5.10 p.m. the same day.
After the autopsy findings were known, the following history was obtained from the patient’s daughter:
It all happened so. very quickly. Mother was quite well up till April, 1952. She complained of feeling tired, so I took her along to the local doctor. He found that she had blood pressure. [The local practitioner states that the patient had suffered from blood pressure for some years.] In May mother noticed that she had diffi- culty in getting up stairs. I noticed that her face started to swell and became very red. Her features broadened and I took her to the doctor again. He found that she had diabetes. Mother’s ankles then began to swell and she bled “internally”. The hair on my mother’s arms and, over the last two months, the hair on her face, grew very thick.
When questioned, the daughter said that her mother had always had a slight growth of facial hair, but it had increased greatly with this illness. She thought that she had first noticed the increased growth of the hair on the arms twelve months earlier. Her mother had gained a lot of weight. There was no family history of hypertension or diabetes.
Post-Mortem Report.
The autopsy was performed thirteen hours after death. The body weight was 73-5 kilograms (162 pounds) and the height 154.9 centimetres (five feet one inch).
The body was that of a short, elderly, obese female. The skin of the face, shoulders and neck was a reddish- purple colour. There was a heavy growth of short-cropped hair on the upper lip, the chin and the sides of the face, and of long hair on the forearms. The abdomen was extremely distended and tympanitic. There were several
1
2
3
3
4
ILLUSTRATION TO THE ARTICLE BY RICHARD FLYNN AND LEO FLYNN.
ILLUSTRATION TO THE ARTICLE BY RICHARD FLYNN AND JOHN H. HALLIDAY.
4986
15451
GHY
ILLUSTRATIONS TO THE ARTICLE BY IAN F. POTTS, M.S., F.R.C.S.
non-pigmented striæ present on the lower abdominal wall. The lower limbs were grossly swollen and pitted deeply on pressure. There was a slight pitting œdema of the dorsum of the hands.
The thyroid gland was of normal size and the right lobe contained a small white nodule measur- ing 0-8 centimetre in diameter. The right pleural cavity con- tained 284 cubic centi- metres of a straw- coloured effusion. Both lungs were intensely congested. A few small isolated yellow nodules were scattered throughout the lung tissue. The heart (340 grammes) was slightly enlarged, mainly owing to hypertrophy of the wall of the left ven- tricle, which measured 1.8 centimetres at the anterior papillary muscle. The mitral ring was slightly dilated. The coronary arteries and the aorta were affected by a slight degree of atheroma.
A large amount of free air escaped when the peritoneal cavity was opened; it also contained 2.27 litres of a turbid, reddish- brown fluid. The peri- toneum of the pos- terior abdominal wall, of parts of the lesser omentum and of the small bowel, was slightly congested. Numerous soft, yel- lowish deposits of newgrowth were scat- tered throughout the peritoneal cavity.
There was a large oval ulcer (3.5 by 3.0 centimetres), which had perforated, on the posterior wall of the body of the stomach (Figure I). There were no adhesions between the stomach and the peritoneum of the posterior wail of the lesser sac. There were a few small, isolated deposits of newgrowth in the liver. The spleen and the pancreas appeared normal.
1
2
3
4
5
6
7
8
9
1
2
3
The right adrenal gland was small but otherwise normal. The left adrenal gland (Figure II) was completely replaced by a soft, yellowish, encapsulated, bun-shaped tumour measuring 8.5 by 7.0 by 5.0 centimetres. The cut surface was yellow and there were numerous areas of hæmorrhage and necrosis. A large vein passed from the medial border
of the tumour into the left renal vein. The left adrenal vein and the left renal vein were completely filled with tumour tissue, which extended into the inferior vena cava for a distance of 2.0 centimetres.
The kidneys were of normal size. Their capsular surfaces were finely granular and the cortices were slightly narrowed. The left kidney was not infiltrated by the adrenal tumour.
The uterus was uni- formly enlarged and measured 10.0 by 5-0 by 4.0 centimetres. The endometrium was slightly hæmorrhagic. The vaginal surface of the cervix was irregular and covered with a thick, brown, mucoid exudate. Numerous small cysts containing a brown mucoid secretion were present in the cervix. The ovaries, bladder and rectum appeared to be normal.
The pituitary gland, which was damaged while being removed from the body, and the brain appeared to be normal. The bones were not examined. There was X-ray evi- dence of secondary deposits in the ribs.
Histological Findings.
Dr. R. Finlay-Jones reported in the follow- ing terms on the sec- tions.
Examination of the left adrenal tumour showed the growth to be a cortical car- cinoma. The pattern of the growth in some regions resembled that of the normal gland, the cells being ar- ranged in anastomos- ing cords, separated by blood-filled sinuses (Figure III). In the tumour cells a moderate degree of pleomorphism was ap- parent (Figure IV). They were mainly 7 4 5 6 round or polyhedral with abundant eosino- philic cytoplasm and eccentric hyperchro- matic nuclei. Large multinucleated cells were fairly numerous. A special stain (Broster-Vines) demonstrated fuchsinophile granules in many cells.
The perforation in the stomach was lined with necrotic tissue. Fibroblastic proliferation in the adjacent stomach wall and infiltration with lymphocytes and plasma cells
were apparent. The absence of scar tissue indicated acute ulceration.
The sections of the pituitary gland were not satisfactory. Crook’s hyaline change in the basophile cells was not present. There were secondary carcinomatous deposits in the liver, lungs, thyroid and omentum. There was a slight degree of venous congestion in the liver and lungs. The endometrium was of a non-secretory type. A slight degree of adenomyosis was present. In the kidneys there was a mild degree of nephrosclerosis, with slight hypertensive changes in the arterioles.
Summary of Post-Mortem Findings.
The post-mortem findings could be summarized as follows: (i) acute peritonitis, a sequel to the perforation of an acute gastric ulcer; (ii) a primary adrenal cortical carcinoma with metastases in the peritoneum, omentum, liver, lungs and thyroid; (iii) hypertensive congestive cardiac failure; (iv) adenomyosis; (v) chronic cystic cervicitis.
Discussion.
Kenyon (1944) has described six possible syndromes which may be associated with adrenal cortical carcinoma: (a) the adreno-genital syndrome; (b) Cushing’s syndrome; (c) mixed clinical pictures, including features of the first two; (d) single or isolated endocrine disturbances-for example, diabetes; (e) feminizing syndromes; (f) tumours without endocrine manifestations.
In this case the plethora, the rounding of the facies, the hirsutism, the obesity, the diabetes and the value for the urinary 17-ketosteroid excretion (which was slightly raised for a woman of her age-Dorfman and Shipley, 1950), and possibly the œdema, together may be taken as evidence of hormone production by the adrenal tumour. Some of the features of Cushing’s syndrome (Cushing, 1932) are present, but the case may best be regarded as an example of Kenyon’s third group, the mixed clinical pictures.
The gastric ulcer was relatively acute, and apparently developed during the terminal illness. The following evidence suggests that there may be a relationship between it and the adrenal carcinoma.
1. The manifestations of Cushing’s syndrome are thought to be principally due to an excess of adrenal gluco-corticoid hormones (Albright, 1942-1943). Overdosage with cortisone (a gluco-corticoid) has reproduced many of the features of Cushing’s syndrome in some subjects (Williams, 1951).
2. The administration of ACTH and cortisone is asso- ciated with a great increase in the concentration of gastric pepsin and acid. The effect of ACTH presumably is due to an increase in the secretion of adrenal gluco-corticoids. Spiro, Reifenstein and Gray (1950) found that the adminis- tration of ACTH increased the excretion of uropepsin in normal subjects and in subjects with peptic ulcers, but did not increase the low uropepsin excretion found in patients with adrenal insufficiency, although cortisone did. Uro- pepsin represents the endocrine fraction of pepsinogen, and its rate of excretion in the urine varies with the rate of excretion of gastric pepsin (Janowitz and Hollander, 1951). These effects of ACTH and cortisone on gastric secretion were confirmed by Gray et alii (1951) who found that the administration of ACTH to humans was associated with a pronounced increase in the basal and nocturnal secretion of acid and pepsin approximating 200%. Cortisone was capable of producing a similar though less pronounced response. The maximum acid and pepsin effects were observed after seven to fourteen days of continuous cortico- trophin therapy.
3. The effect of these hormones on gastric secretion is associated with the development of peptic ulcer in a significant percentage of subjects receiving the hormones, estimated by Halstead (1952) to be 4%.
Beck et alii (1950) first reported the occurrence of a perforated ulcer in association with ACTH therapy. Since then numerous cases have been reported of the occurrence,
during or immediately after courses of ACTH or cortisone therapy, of a recrudescence or exacerbation of ulcer symp- toms, of hæmorrhage from or perforation of a chronic peptic ulcer and of the development of peptic ulcer de novo which sometimes perforates (Gray et alii, 1951; Halsted, 1952; Habif et alii, 1950; Sandweiss et alii, 1950; Smyth, 1951; Lubin et alii, 1951; Kirsner et alii, 1952).
It is reasonable to infer that there was in this case, and that possibly in all cases of Cushing’s syndrome, what- ever the primary ætiology, an increase in the secretion of gastric pepsin and acid, which may lead to the development of a peptic ulcer in a susceptible subject.
Summary.
1. The case is reported of an elderly woman with an adrenal cortical carcinoma producing some of the features of Cushing’s syndrome, who died from a perforated peptic ulcer.
2. Evidence is given that the administration of adrenal gluco-corticoid hormones is capable of producing some of the features of Cushing’s syndrome and peptic ulcers in susceptible individuals.
3. The relationship between the ulcer and the adrenal cortical carcinoma is discussed.
Acknowledgements.
I wish to thank Dr. E. H. Stokes, senior physician at Sydney Hospital, for permission to publish this case. I am also indebted to Dr. H. M. Whyte and Dr. W. Simmonds for criticisms and suggestions in the preparation of this paper, and to Mr. R. Money for the illustrations.
References.
ALBRIGHT, F. (1942-1943), “Cushing’s Syndrome, Its Pathological Physiology, Its Relationship to Adreno-genital Syndrome, and Its Connection with the Problem of Reaction of Body to Injurious Agents (‘Alarm Reaction’ of Selye)”, “Harvey Lectures”, 123.
BECK, J. C., BROWNE, J. S. L., JOHNSON, L. G., KENNEDY, B. J., and MACKENZIE, D. W. (1950), “The Occurrence of Peri- tonitis during ACTH Administration”, Canad. M.A.J., 62 : 423.
CUSHING, H. (1932), “Basophil Adenomas of the Pituitary Body and Their Clinical Manifestations (Pituitary Basophilism)”, Bull. Johns Hopkins Hosp., 50 : 137.
DORFMAN, R. Z., and SHIPLEY, R. A. (1950), “17-Ketosteroids in Human Urine”, “Progress in Clinical Endocrinology”, edited by S. Soskin, 205.
GRAY, S. J., BENSON, J. H., REIFENSTEIN, R. W., and SPIRO, H. M. (1951), “Chronic Stress in Peptic Ulcer”, J.A.M.A., 147 : 1529.
HABIF, D. V., HARE, C. C., and GLASSER, G. H. (1950), “Per- forated Duodenal Ulcer Associated with Pituitary Adreno- corticotropic Hormone Therapy”, J.A.M.A., 144: 996.
HALSTED, J. A. (1952), “The Effects of ACTH and Cortisone in Diseases of the Digestive System”, M. Clin. North America, July, 1069.
JANOWITZ, H. D., and HOLLANDER, F. (1951), “Relation of Uropepsinogen Excretion to Gastric Pepsin Secretion in Man”, J. Appl. Physiol., 4 : 53.
KENYON, A. T. (1944), “Adrenal Cortical Tumours-Physiologic Considerations”, Surgery, 16 : 194.
KEPLER, E. J., et alii (1948), “Adrenal Cortical Tumour Asso- ciated with Cushing’s Syndrome: Report of a Case with Metabolic Studies and Remarks on the Pathogenesis of Cushing’s Syndrome”, J. Clin. Endocrinol., 8 : 499. KIRSNER, J. B., KLOTZ, A. P., and PALMER, W. L. (1952), “Unfavourable Course of Gastric Ulcer During Adminis- tration of ACTH and Cortisone”, Gastroenterology, 20 : 27. LUBIN, R. I., MISBACH, W. D., ZEMKE, E. M., HAMMERSTEIN, J. F., and HELLER, B. I. (1951), “Acute Perforation of Duodenal Ulcer During ACTH and Cortisone Therapy”, Gastro- enterology, 18 : 308.
SANDWEISS, D. J., SALTZSTEIN, H. C., SCHEINBERG. S. R., and PARK, A. (1950), “Hormone Studies in Peptic Ulcer : Pituitary Adrenocorticotropic Hormone and Cortisone”, J.A.M.A., 144 : 1436.
SMYTH, G. A. (1951), “Activation of Peptic Ulcer during Pituitary Adrenocorticotropic Hormone Therapy”, J.A.M.A., 145 : 474.
SPIRO, H. M., REIFENSTEIN, R. W., and GRAY, S. J. (1950), “The Effect of Adrenocorticotropic Hormone upon Uropepsin Excretion”, J. Lab. and Clin. Med., 35 : 899.
WILLIAMS, R. H. (1951), “Hyperadrenocorticism”, Am. J. Med., 10 : 612.
Legends to Illustrations.
FIGURE III .- Section of the adrenal tumour, showing a slight resemblance to the normal adrenal architecture.
FIGURE IV .- Section of the adrenal tumour illustrating the pleomorphism of the cells.