20996023

ADRENOCORTICAL CANCER WITH UNDU- LATING FEVER IN ADDISON’S DISEASE

A. P. CAWADIAS, O.B.E., M.D., F.R.C.P. London, England

T HE following observation helps us to elucidate certain points in the natural history of Addison’s disease, particularly the rôle of adreno- cortical cancer in the genesis of this disease and the significance of un- dulating pyrexia in the Addisonian clinical picture.

CLINICAL OBSERVATION

G. P., 34-year-old male, was observed principally during the first four months of 1945. His whole history can be divided into five phases, (a) a prodromic phase: (b) a phase of onset of distinct symptoms, (c) a phase of severe Addisonian crisis, (d) a phase of sub- acute Addisonism, and (e) a terminal phase of Addisonian coma.

Personality, constitution. The patient was a Greek from the Greek islands. There was nothing particular in his heredity nor in his previous history save for an appendectomy done in 1940. He complained at that time of vomiting and pains. The appendix showed chronic lesions.

Physically he was a “pycnic,” brevilinear, of normal stature, muscularly powerful, violent and a little aggressive. He had a tendency to overweight, weighing more than 12 stone in 1943. His blood pressure, taken during a health examination in 1940, was 100/70. His blood group was O. In his early youth he had joined the Merchant Navy and had travelled extensively. He was successful in business, active and extrovert, keen on amus- ing himself and gambling. He was happily married, but his wife and child were cut off from him, as they were in Athens during the occupation of Greece, and this worried him intensely. He was rather hypersexual but not a heavy smoker nor drinker.

Prodromic phase, 1942-November, 1944. Towards the beginning of 1942 the patient had vague symptoms of asthenia and occasional vomiting. He also had sudden atacks of mental depression. In his own words, “I used to be taken with profound melancholy. I used to cry without any cause or explanation.” He was treated for “dyspepsia,” “nico- tine poisoning,” “neurasthenia and hypotension.” He took some “slimming pills” (thyroid) for a long time. He was in fact rather obese and at the same time muscular. There was no diminution of potency.

Onset of characteristic symptoms, November, 1944-January 11, 1945. In November, 1944, he entered University College Hospital because his depression and vomiting had become accentuated. Clinical and radiological exploration of the digestive and respira- tory systems was negative, and findings were normal in the nervous, circulatory and urinary systems. Electrocardiogram normal. Pressure not noted. Urine showed no al- bumen. Blood showed polyglobulin, to which little attention was paid. Erythrocyte count was 7,200,000 per cu. mm., with 90% haemoglobin. Leucocyte count was 6,000 with polymorphs 34%, lymphocytes 56%, and mononuclears 10%. Blood sugar was 111 mg. percent. Blood platelets were 400,000 per cu. mm .; bleeding and clotting times, normal. At onset, temperature was lower than normal, about 97ºF., but on November 30 it rose to 100ºF.

Received for publication March 28, 1946.

The tonsils were incriminated as the principal aetiological factor of the condition, and tonsillectomy was performed on December 7, 1944. After the operation the temperature rose to 105°F. but fell two days later to about 100ºF. Bronchopneumonie symptoms de- veloped; asthenia and vomiting became accentuated. He was seen in consultation with Dr. Cawadias on January 9, 1945. Diagnosis: Addison’s disease in a condition of crisis (post-operatory); bronchopneumonia.

Addisonian crisis, January 11-15, 1945. The patient was transferred to the London Clinic. The condition was rapidly becoming worse. Mental confusion was verging on coma. Vomiting was intense. Heart was normal, but pressure was 55/35 mm. Hg. Cough and expectoration with râles on the right base were present. There was an intense pig- mentation of the skin, of “bronzed” type. Large plaques of melanotic pigmentation were present on the buccal mucosa and lips. Temperature was 100ºF .; pulse, imperceptible. The blood showed 5,680,000 erythrocytes per cu. mm. with 60% haemoglobin and marked hypochromasia; leucocyte count was 7,333 with 54% neutrophils, 39% lymphocytes, 6% monocytes. Intensive treatment with adrenocortical extract was instituted (Eucor- tone, 100 cc. per 24 hours with saline infusions and Redoxon forte injections). Following this treatment the patient became conscious. Vomiting diminished. Blood pressure on January 13 was 72/10 mm. Hg.

Phase of sub-acute Addisonism, January 15 - April 22, 1945. During this phase the patient showed a general condition of balanced Addisonism interrupted by a few paroxysms. He was maintained by high doses of adrenocortical extract (40-60 cc. daily) with thiamine hydrochloride injections, ascorbic acid and salt. He did not react so well to DOCA. Any diminution of the adrenocortical extract caused aggravation of the con- dition. In fact we had the impression of dealing with an adrenalectomized animal need- ing its constant supply of adrenocortical extract. Thanks to the kindness of Sir Alexander Fleming a course of penicillin was instituted in March (1,000,000 units) to determine whether the high temperature was due to a secondary, even undetermined, infection. No result except from a psychological point of view was obtained.

The paroxysms (crises) were brought on by emotional factors (news and thoughts about his family in Athens), by diminution of the adrenocortical extract, once after pyramidon intake and once during a heat wave. During the crises digestive and nervous symptoms were aggravated.

The general course of the Addisonism was as follows.

The general asthenia was constant, and the patient was usually in bed, although com- fortable. Wasting was marked only in the last weeks. Pigmentation of the skin improved greatly with treatment but became more intense in the last month (April) notwithstand- ing treatment.

The whole course was febrile. Hyperthermia occurred in the form of “undulating fever.” These waves occurred during the whole period when he was under our observa- tion. They were separated by very short intervals (1-3 days at most) of normal tempera- ture. They were not very regular. At onset the crest of the wave reached 101-102ºF. Later it could reach 104°F. Only two rigors were noted. There was no perspiration. The pulse was not accelerated in relation to the elevation of temperature. With 103ºF. the pulse rate was 100 per min., with 104ºF., also 100 per min. The severity of the symptoms was not parallel with the temperature, and in many instances the patient felt well not- withstanding very high temperatures. Respirations were between 24 and 32 per min.

Blood cultures were negative. Cultures from the throat showed neither haemolytic streptococci nor any other pathogenic micro-organism. The only bacteria present were those normally present in the throat. Quantitative tests showed a slight increase in the

number of pneumococci, but otherwise the relative numbers of bacteria were normal. All agglutination reactions were negative.

A further careful search for any pathogenic micro-organism, made in Sir Alexander Fleming’s laboratory at St. Mary’s, was negative. Penicillin did not influence the tem- perature.

The mental status showed important features. There was a definite change of per- sonality. The patient became anxious about money matters, and ideas of ruin filled his mind (although in fact he was very wealthy and before his illness spent freely). He was emotional but not definitely discouraged or aboulic. Mental paroxysms occurred without any particular reason, taking the form of apathy, confusion, excitation or hallucinations. During the attacks of apathy he was indifferent to his environment, he did not answer questions and was not interested in seeing anybody. From apathy he would pass into confusion with disorientation. Hallucinations were a striking feature. He would go to the window and point out to the nurse imaginary men walking on the roof of the house opposite. Twice he told me that he had seen a man stab another in the street. On April 2 he dressed himself and wanted to leave the nursing home because he was seeing serpents in his room and the nurse was giving him “electric currents.” He insisted on changing the bed clothes because “the nurse was always putting him on a rubber sheet.” He complained of a peculiar smell which he could not define but said was due to the fact that they were bringing him things from the theatre (the mouse smell described in Addi- son’s disease did not occur). Twice he got up at night and tore up pound notes.

The heart remained normal during the whole period except for extra systoles, which occurred in March. Pressure was well maintained at 90/50 mm. Hg. Pulmonary symp- toms of cough, expectoration and râles continued. There was no Koch’s bacillus in the sputum.

The urinary system, apart from water retention, showed no abnormality. There was a faint trace of albumen in the urine and a slight centrifugal deposit containing a few granular casts, detached renal cells and isolated blood discs. No leucocytic excess and no crystals.

The digestive symptoms consisted principally in vomiting, usually without effort. This occurred in bouts but was rare during treatment, and the patient could take sub- stantial food, especially as his appetite was good except during rare periods of anorexia. On three occasions he had hiccups lasting two to three days. Stools were fairly normal.

The erythrocytic syndrome showed interesting developments, and a hypoglobulin and hypochromic anaemia, masked at onset by the haemoconcentration, became manifest. The red cells, which during the initial crisis were 5,680,000 per cu. mm. diminished pro- gressively. January 31, the erythrocyte count was 4,400,000 per cu. mm. with 80% haemoglobin; on April 24, 2,480,000, with 36% haemoglobin. Hypochromasia, anisocyto- sis and poikilocytosis were marked. Sedimentation rate on January 30 was: one hour, 130 mm .; two hours, 140 mm. (Westergreen); on March 28, one hour, 60 mm. Trans- fusion was considered but rejected for fear of untoward reactions.

The white cells also showed various changes. On January 16 the leucocyte count was 9,600 per cu. mm .; polymorphs, 48%; lymphocytes, 45%; hyalines, 0.4%. On January 31, the leucocyte count was 22,000 oer cu. mm .; polymorphs, 62.5%; lymphocytes, 29%; hyalines, 0.5%. In February, the leucocyte count was 10,500 per cu. mm .; polymorphs, 55%; lymphocytes, 42%; mononuclears, 2%; eosinophiles, 1%. On April 24, the leucocyte count was 12,900 per cu. mm .; polymorphs, 59%; lymphocytes, 36%; monocytes, 4%; eosinophiles, 1%. This polynucleosis corresponded to the pulmonary symptoms, and up to a certain point to the fever.

The study of the fluid intake and urinary output in January and February showed retention of water, the output being from 300 cc. to 900 cc. (10 to 30 ounces) less than the intake.

The metabolic syndrome, which could not be studied thoroughly owing to the con- dition of the patient, is indicated by the following figures.

Sugar in blood	16.1.45	111 mg. per cent.
Urea in blood	5.4.45	101 mg. per cent.
Creatine in urine	20.1.45	200 mg. per cent per 24 hours.
Creatinine in urine	20.1.45	1,340 mg. per cent per diem.
Sodium in blood serum	5.4.45	294 mg. per cent.
Chlorides in serum	5.4.45	549 mg. per cent.
Sodium in urine	20.1.45	422 mg. per cent in 24 hours.
Potassium in blood	5.4.45	21.2 mg. per cent.
Porphyrin in urine, test	positive,	but no spectroscopic evidence of
haematoporphyrin.

Terminal syndrome. Despite continuation of intensive treatment with adrenocortical extract the condition deteriorated gravely and nearly suddenly in the second fortnight of April. The patient entered into deep coma on April 22 and died on April 25. Hyper- thermia persisted to the end.

To sum up, a “pycnic” individual, aged 34 years, showed for nearly two years occa- sional symptoms of depression, weakness and vomiting. In the last two months asthenia and vomiting became accentuated, and pigmentation and polyglobulinaemia occurred. After tonsillectomy there was a typical Addisonian crisis of comatose form from which he recovered, thanks to intensive adrenocortical extract therapy. After that, for three and a half months a severe Addisonian syndrome developed, interrupted by paroxysms. Leading symptoms were intense skin and mucosal pigmentation, asthenia, hypotension (corrected up to a point by treatment), attacks of vomiting and hiccough, attacks of hallucinations, hypoglobulinic and hypochromic anaemia, and an intense undulant fever. Blood sugar and electrolytes were maintained at fairly normal figures. Without any special occasional cause, life terminated in coma.

Anatomopathological Examination

Autopsy was performed by Dr. Neumark (St. Mary’s Hospital Pathological Labora- tory). The pathological examination was made by Professor Newcomb and Dr. Neu- mark.

Cardiovascular system

There was a brownish color of the myocardium. The endocardium and valves were clean. All chambers contained post-mortem clots. Slight atheroma were in the aorta. Histologically there was some brown atrophy.

Respiratory system

Macroscopically there was some chronic bronchitis. The lungs showed some emphy- sema macroscopically. There was bronchopneumonia with much pulmonary oedema mi- croscopically. Pleura was clear except for slight right basal adhesion.

Alimentary system

Nothing abnormal in oesophagus, stomach, or intestines. The para-aortic lymph glands were enlarged, whitish, soft. Macroscopically chronic inflammatory reaction. Liver had a nutmeg pattern; was rather fatty at periphery of lobule. Microscopically there was an in-

crease of peripheral fat in hepatic lobules. There was a small gland at the junction of hepatic and cystic ducts. Microscopically this showed inflammatory changes, and on the peripheral sinus there was a small collection of cells resembling those found in the adrenal tumour. The gall bladder contained dark green bile; the ducts were patent. The pancreas was normal.

Left suprarenal

This measured 6.5 cm. X4 cm. X3 cm. It was a hard, well-encapsulated mass, and had no resemblance to the suprarenal except its shape. On section it had a similar appearance to the mass on right kidney. Microscopically there was very little resemblance to a normal adrenal. There was extensive necrosis, some fibrosis and, between the fibrous tissue cells, there were collections of cells arranged mainly in trabecular fashion, and some were in alveoli. There were no tubules. These cells varied in size and shape. Most were anaplastic, some possessing more than one nucleus. Some were almost spindle- shaped, others globular. Some stained intensely black with Weigert’s haematoxylin, but others did not take up the stain. Mitotic figures were not numerous. Sections frozen and stained with Sudan III and haematoxylin showed that the centre of the adrenal con- tained much fat, but fat was not a prominent feature of the tumour cells.

Right suprarenal

This was an irregular mass, partly broken up, and was removed with difficulty. It measured about 4 cm. in diameter. Its microscopical appearance was similar to that of the left suprarenal, but it was more necrotic.

Left kidney

This measured 10.5 cm. X5 cm. X4 cm. Microscopically it showed ischaemic fibrosis.

Right kidney

This measured 12 cm. X6.5 cm. X5 cm. The upper pole was replaced by a mass of about 5 cm. diameter, which on section was definitely circumscribed. The mass was hard, whitish yellow, somewhat whorled and broken down in parts. Microscopically this tu- mour was not encapsulated and consisted of tissue like that described for the adrenals (principally the left adrenal, as the right adrenal was very necrotic). There was much ne- crosis. Staining with Sudan III showed the same distribution of fat presented particularly by the left adrenal. This tumour pressed on the liver, but as shown by microscopical ex- amination, although it compressed the liver lobules, it did not invade them.

The diaphragm showed a great deal of fibrosis but no invasion by the tumour. Although there were many collections of small round cells in the muscle and even on the pleural surface, no tumour cells were found in these sites.

The spleen was septic, with many polymorphs and a good many eosinophiles. Prostate was normal. The nervous system, thyroid and pituitary were not examined.

Pathological diagnosis. Professor Newcomb, who examined these preparations to- gether with Dr. Neumark and myself, concludes that this is a case of carcinoma of the adrenals with metastases in the right kidney.

DISCUSSION

Three important points in the natural history of Addison’s disease have to be considered on the basis of this clinical study combined with the critical evaluation of allied observations.

The possibility of adrenocortical carcinoma as a cause of Addison’s disease.

Addison considered that cancer could give rise to the disease he had described. Wilks, however, and principally Greenhow rejected this etiol- ogy. In his Croonian lectures at the Royal College of Physicians in 1875 Greenhow (5), after discussing the cases reported as cancer of the adrenals giving rise to Addison’s disease, rejected all of them. Three of the cases cited, however, appeared to him of difficult interpretation, and he wrote, “If these three cases were in truth cases of cancer of the suprarenal cap- sules they are the only cases on record in which cancerous disease of these organs has ever given rise to the constitutional symptoms and bronzing of the skin characteristic of Addison’s disease.” This opinion has pre- vailed, and Rowntree and Snell (10) write in their classical monograph that carcinoma is “a negligible consideration in the cause of Addison’s disease.”

I believe that this conception should be changed, and the possibility of rare cases of Addison’s disease due to cancer of the adrenals should be accepted. In fact, in 1908 I communicated with Galliard (4) a case of acute Addison’s disease in which autopsy showed carcinoma of one ad- renal gland and distinctive lesions of the adrenocortical tissue of the op- posite gland. In 1909 Winkler (12) recorded two cases of fully developed Addison’s disease associated with cortical tumours of the adrenal gland. In 1930 Anderson (1) reported a case of fatal hypoglycaemia in which the blood sugar dropped to 0.04 per cent before ending in hypoglycaemic coma despite the use of glucose and epinephrine, and in which a tumour was found in the left gland, the right gland being “smaller and more fibrous than usual.” In 1940 McGavack (6) described a case of of mascu- linisation terminating in a fatal “Addisonism” and malignant cachexia. Autopsy showed a massive masculinising primary carcinoma of the cortex of the adrenal gland with apparently complete destruction of all normal glandular tissue, moderate atrophy of the left adrenal gland and metastases to the liver, lungs and pleura.

The observation forming the basis of this paper is a further demonstra- tion of the possibility of cancer giving rise to Addison’s disease, and prob- ably represents the most complete case described. It should be remembered that there are also rare cases of malignant phaecochromocytoma giving rise to Addison’s disease, as shown by McGavack (7). Cases, also reputed to be Addisonian have been described as caused by tumours involving the solar plexus, Fowler (3), Bucknill (2), but as far as I can gather from these observations they were of cases of melanodermia and not of real Addison’s disease. Secondary cancer of the adrenals can give rise

also to Addison’s disease according to some authors, but more clinical work is necessary to clarify this point.

Fever in carcinogenic Addison’s disease

We can go a step further and consider that fever is often characteristic of such Addisonian adrenocortical cancer. An undulating pyrexia of four months’ duration was a characteristic of our case. Fever has been de- scribed in adrenocortical cancer in general. The case of Trémolières and his collaborators (11) developed as a severe septicaemia. At autopsy a bi- lateral adrenocortical carcinoma with multiple metastases was found. McGavack (6) also cites cases with fever in his non-androgenic adreno- carcinomas. René Puig (8) described a case developing as an “undulant fever” and shown at autopsy to be a bilateral adrenocortical carcinoma with multiple metastases. It is interesting to compare these observations with that of Roch and Bickel (9), who observed in a woman operated for carcinoma of the breast an “undulant fever” occurring four months after the operation and lasting for six months. Many years ago I observed a case of left hypernephroma with distinct “undulant fever” [sic.] in the Evangelismos Hospital of Athens. At first the enlarged left kidney was taken for an enlarged spleen, and the first diagnosis was one of Brucellosis (Mediterranean fever).

In all published observations of adrenocortical carcinoma with fever no agent of secondary infection was found, and in our case in particular a very careful search was made. It is probable that fever in these cases is due to absorption of necrotic tissue. In fact in all observations, including our own, necrosis was a prominent pathological finding.

Addison’s disease is usually afebrile or hypothermic. High temperature before death has been described, however, and some clinicians mention cases with “unexplained pyrexia.” McGavack writes that Addison’s disease should be considered in the differential diagnosis of cryptogenetic fevers. At all events, in cases of Addison’s disease with fever the cancerous etiology should be considered.

The mental syndrome in Addison’s disease

Descriptions of the psychological manifestations in Addison’s disease do not seem to be very complete. Discouragement and depression are de- scribed. A more careful investigation in our case showed changes of per- sonality, attacks of unexplained melancholia preceding other symptoms by a long time, and hallucinations. Clinical science would gain by a more precise investigation of such psychological features, because the cerebral cortex seems a very delicate register of metabolic disturbances. It is true that all psychological manifestations in endocrine diseases are not of

purely endocrine-metabolic origin. The psychological personality of the patient enters into consideration, as much is due to his particular psycho- genic reactions.

Treatment was of course of no avail. However, adrenocortical extract maintained a survival of the same form, as it maintains the survival of adrenalectomized animals. The electrolyte metabolism was normal even a few days before death, and blood sugar was normal even during the initial severe Addisonian crisis. This is one more argument for accepting that an important and hitherto unknown factor in the adrenal cortex distinct from the electrolyte, carbohydrate and genital factors is responsible for “survival” and that deficiency of this factor in adrenalectomy and Ad- dison’s disease causes death.

ACKNOWLEDGEMENT

I am very grateful to Sir Alexander Fleming, F.R.S., Professor W. D. Newcomb, M. D. and Dr. E. Neumark for the help they gave so freely in this case.

REFERENCES

1. ANDERSON, A. B. A tumour of the adrenal gland with fatal hypoglycaemia. Am. J. M. Sci. 43: 71 (1930).

2. BICKNILL, F. Addison’s disease due to malignant involvement of the solar plexus. Brit. M. J. 2: 206-207 (1934).

3. FOWLER, J. K. Lymphadenosis with brown pigmentation of the skin (G. E. Paget, Physician to Addenbrooke’s Hospital, Cambridge). Lancet. 1: 258 (1879).

4. GALLIARD, L., and A. P. CAWADIAS. Bull. et mém. Soc. méd. d. hôp de Paris. 26 (3rd series): 32 (1908).

5. GREENHOW, E. H. Addison’s disease (Croonian Lectures). London, Longman, 1875, xiv, 212 pp.

6. McGAVACK, T. H. Masculinising and non-masculinising carcinomata of the cortex of the adrenal gland. Endocrinology. 26: 396 (1940).

7. McGAVACK, T. H., J. W. BENJAMIN, F. D. SPEER, and S. KLOTZ. Malignant phaeo- chromocytoma (paraganglioma). Report of a case simulating carcinoma of the ad- renal cortex with secondary adrenal insufficiency. J. Clin. Endocrinol. 2: 332 (1942).

8. PUIG, R. Adrenocortical cancer with multiple metastases and undulant fever. Bull. et mém. Soc. méd. d. hôp. de Paris. 13: 194 (1937).

9. ROCH, M., and G. BICKEL. Prolonged undulating fever of carcinomatic origin, ter- minal pernicious anemia. Bull. et mém. Soc. méd. hôp. de Paris. 34: 806 (1923).

10. ROWNTREE, L. G., and A. M. SNELL. A clinical study of Addison’s disease. Phila- delphia, Saunders, 1931, 317 pp.

11. TRÉMOLIÈRES, F., A. TARDIEU, A. CARTEAUD, and E. NORMAND. Acute generalised cancer of adrenocortical origin, septicaemic form. Bull. et mém. Soc. méd. d. hôp. de Paris. 46: 710 (1930).

12. WINKLER, CARL. Die Gewachse der Nebennieren. Jena, Gustav Fisher, 1909.