ADRENAL CORTICAL CARCINOMA SIMULATING A PHÆEOCHROMOCYTOMA
BY PHILIP L. ROBINSON
SENIOR MEDICAL REGISTRAR, CLATTERBRIDGE HOSPITAL, BEBINGTON, CHESHIRE AND E. T. BAKER-BATES
CONSULTANT PHYSICIAN, CLATTERBRIDGE HOSPITAL, BEBINGTON, CHESHIRE
CONSIDERABLE attention has been directed within the last few years to phæochromocytomas, and, now that the extremely variable clinical picture is better appreciated, more cases are being diagnosed. The condition has been well reviewed by Belt and Powell (1934), Mackeith (1944), Calkins and Howard (1947), Blacklock, Ferguson, Mack, Shafar, and Symington (1947), Bauer and Belt (1947), Cahill (1948, a), Walton (1950), and Bartels and Cattell (1950). The last-named authors consider that some 200 cases have now been reported in the literature. Malignant phæochromocytomas are extremely rare ; Cross and Pace (1950) give references to only 8 cases and add a ninth.
We now report a case which clinically was diag- nosed as a phæochromocytoma, although presenting certain unusual features, and which at autopsy was found to be malignant, with secondary deposits in the lungs. The microscopical appearance of the tumour, however, was not in keeping with a phæo- chromocytoma, but was undoubtedly that of an adrenal cortical tumour. In a review of the literature we have been unable to find any similar clinical picture produced by a suprarenal cortical tumour.
CASE REPORT
PREVIOUS HISTORY .- A male patient, born in 1918, was first seen by one of us at out-patients in 1947. We then obtained a history, which was later elaborated by Army medical records, that he had been perfectly well until 1942, when serving in India. At that time he developed pain in the left side of the chest and was in hospital for a month. A similar attack occurred in May, 1944, when an emergency appendicectomy was performed. A third identical attack of pain in the left side of the chest and back occurred in January, 1945, and a diagnosis of recurrent pericarditis was made. In March, 1945, he felt well, his blood-pressure was 112/78, but a ’ pericardial rub ’ was reported as still present. The white-cell count was 7400, the blood sedimentation rate was 5 mm. per hour, and screening showed no significant abnormality in the heart shape except for slight unfolding of the aorta. An electrocardiogram showed sinus rhythm with slight ST elevation in leads I and IV, and slight depression in lead III. An Army medical specialist reported “dry pericarditis, with two similar attacks in the last three years-aetiology uncertain, possibly tuberculous “. He was evacuated to the United Kingdom, and re-investigated in May, 1945, when his blood-pressure was 120/80 and no friction rub was heard. An electrocardiogram showed no change from the previous record. He proceeded on embarkation leave, but was re-admitted to hospital in July, 1945, with a fourth attack of pain in the left sub- mammary region and left side of the back, severe and stabbing in nature, aggravated by coughing and breathing. There was some tenderness in the left hypochondrium, his blood-pressure was 120/70 and no pericardial rub was audible. The urine contained a trace of sugar, and the specific gravity was 1032. The white-cell count was 10,200 per c.mm. and the blood sedimentation rate
6.5 mm. in I hour. A radiograph of the chest, on a portable machine, showed ” no pulmonary lesion, slight degree of general cardiac enlargement “. The Wasser- mann reaction was negative. An electrocardiogram showed a negative T wave in lead III, otherwise normal. In August, 1945, he was invalided out of the Army, with a diagnosis of ‘recurrent pericarditis ‘.
By the time we first saw him in August, 1947, he had had at least two further attacks of chest pain, treated by his own general practitioner in a cottage hospital, who stated that “the attacks came on suddenly without apparent cause or previous failing health “. He described the pain as acute, and said there was quite a marked friction rub during the attack. Between attacks, the patient was said to be breathless on exertion. On examination an ” extra sound ” was heard before the mitral first sound, which was considered to be a form of triple rhythm. His blood-pressure was 135/105, and X-ray examination of the chest showed some generalized cardiac enlargement. The electrocardiogram showed low voltage and flat T3, but was otherwise normal.
In June, 1949, he was admitted to our hospital complaining once more of stabbing pain in the left chest similar to previous attacks, starting in the left pos- terior chest and radiating around to the front, being aggravated by deep breathing. He was in good general condition, apyrexial, pulse 88, respirations 24, and blood- pressure 140/105. Again an ‘impure ’ first heart sound was noted, but he was also thought to have a definite ’ to and fro’ friction sound, which became more distinct a few days after admission, although its exact nature was in considerable doubt. The urine contained no protein and no sugar. The white-cell count was 5,600, and the blood sedimentation rate 5 mm. in I hour (Wintrobe). A radiograph of the chest showed the lung fields to be clear, but once again there was considered to be some dilatation of the aorta. The blood Wassermann was negative, and a barium swallow and meal excluded hiatus hernia. The pain disappeared, but the abnormal heart-sound persisted. He was discharged after four weeks in hospital, diagnosed again as recurrent peri- carditis of obscure aetiology.
We did not see him again until April, 1951, when he stated that since discharge he had had occasional pain in the left chest, and breathlessness on exertion associated with a sensation of tightness in the chest, and frequent vomiting. He had been at work until December, 1950, when he developed tonsillitis followed by a left-sided ’ pleurisy ’ which lasted a few weeks. In February, 1951, he had developed a somewhat different pain in the left lower chest and left side of the abdomen, dull aching in character and lasting anything from a few minutes to a few days at a time, which had occurred frequently. He had often vomited. On the day of admission this pain had become extremely severe, and thereafter was the most prominent symptom. He had lost some weight in the previous six months, and had two days’ severe head- ache the previous week, but otherwise had no other symptoms. A close friend told us later that the patient had often been observed sweating profusely during the previous few years.
ON EXAMINATION .- The patient was of average build, in good general condition, but obviously in severe pain
and sweating profusely. The temperature was normal. There was tenderness in the left hypochondrium and left loin, but no mass could be felt, and the liver, spleen, and kidneys were not palpable. The pulse was regular, but the blood-pressure was 200/140 (R), 180/125 (L). The mitral first sound was reduplicated, and no friction rub was heard. The lungs and nervous system, including the fundi, were normal, and there were no abnormalities of genitalia or secondary sexual characteristics.
COURSE PRIOR TO OPERATION .- He was observed and investigated over a period of 14 days, and was, for most of this time, in apparent very severe pain, unrelieved by pethidine and morphine. He sweated profusely, but
The intravenous histamine and piperoxane tests were against a diagnosis of phæochromocytoma, and pain as severe as this patient was suffering was not appreciated by us at that time as a recognized feature of this condition. Nevertheless, in view of the variable blood-pressure, the excessive sweating, normal temperature, raised fasting blood-sugar and leucocytosis, together with the other negative findings, a tentative diagnosis of phæochromo- cytoma was made, and, after consultation with our surgical colleagues, it was agreed to explore the left suprarenal region.
AT OPERATION (Mr. M. Silverstone) .- Anaesthesia was induced with pentothal and flaxedil and continued
A
B
remained apyrexial. The blood-pressure was found to vary from time to time from 120/90 to a maximum of 260/170, which was recorded whilst under thiopentone, nitrous oxide, and oxygen anaesthesia for cystoscopy and ureteric catheterization. The usual readings in bed were between 130/90 and 200/130.
INVESTIGATIONS .-
Urine (repeated examinations) :-
Protein-a faint trace to 0.3 g. per cent.
Sugar-nil.
Deposits-a fair number of finely granular and hyaline casts seen on one occasion, but usually nothing abnormal.
Blood-urea : 40 mg. per cent, 20 mg. per cent.
Blood-sugar (fasting before breakfast) :-
147 mg. per cent, 154 mg. per cent.
117 mg. per cent, 185 mg. per cent.
White-cell count :-
11,700 per c.mm., 18,300 per c.mm., 15,800 per c.mm. (P., 77 per cent ; L., 14 per cent ; M., 9 per cent.)
Radiography of chest : Slight cardiac enlargement. Some dilatation and unfolding of the aorta.
Straight radiograph of abdomen : No abnormality noted. Intravenous pyelogram : Within normal limits, but left kidney is not well visualized.
Retrograde pyelogram : There was slight rotation of the left kidney, but this was considered to be within normal limits.
Electrocardiogram : Normal.
Intravenous histamine test : Negative.
Intravenous piperoxane test : Negative.
Blood Wassermann Reaction : Negative.
Cerebrospinal Fluid : Fluid, clear. Total protein,
45 mg. per cent. Cells, 2 per c.mm. Gold curve, normal. Wassermann reaction, negative.
with nitrous oxide and oxygen and minimal doses of pethidine. Intravenous saline and blood were given, and blood-pressure readings were taken every two minutes throughout the operation.
The ninth rib was excised and the pleura opened. The left kidney region was explored extraperitoneally, and a large tumour found situated superiorly to the left kidney, and extending across to the midline. The tumour was dissected out with great difficulty, and could not be separated from the kidney. The kidney was therefore excised together with the tumour. Great difficulty was experienced with the medial extension of the tumour, which appeared to involve the aorta.
At the commencement of the operation the blood- pressure was 210/170, with a pulse-rate of 120 per minute. Throughout the operation the diastolic pressure gradually rose towards the systolic and the pulse-rate increased. The injection of piperoxane (5 c.c. ; 10 mg.) on several occasions had no effect on the blood-pressure, which was finally recorded as 210/200 about an hour after the commencement of operation. It thereafter became unreadable, although the pulse was palpable at about 180 per minute for 15 minutes longer. The patient died a few minutes after the removal of the tumour, and attempts at resuscitation with cardiac massage, adrenaline, methedrine, and nikethamide were useless.
AT POST-MORTEM EXAMINATION .- The significant findings were as follows : A considerable number of small nodules scattered throughout both lungs about 3-6 mm. in diameter. Section showed these to be foci of malignant cells indistinguishable from those found in the more cellular parts of the primary tumour. (Fig. 475.) Apart from lymph-glands adjacent to the primary tumour, no other secondary deposits were found. The right suprarenal showed no macroscopical or microscopical abnormality. The kidneys, heart, and other organs
ADRENAL CANCER SIMULATING PHAOCHROMOCYTOMA 401
were also normal. There was no evidence of past or present pericarditis.
DESCRIPTION OF THE TUMOUR REMOVED AT OPERA- TION .-
Macroscopically the tumour was oval and measured 13 x 6 X 7 cm. It seemed to be encapsulated, though the capsule did not appear to be complete. It weighed 396 g. Its cut surface showed a variegated appearance, yellowish translucent areas alternating with areas of
(1944), Cahill (1948, b), Phillips and Ray (1949), Walters and Sprague (1949), and Cahill and Melicow (1950). The clinical pictures described can be classi- fied as follows :-
a. Adrenogenital syndrome ;
b. Cushing’s syndrome ;
c. A mixture of adrenogenital and Cushing’s syn- dromes ;
A
B
necrosis, areas of hæmorrhage, and areas in which the tissue was soft and greyish in appearance.
Microscopically the tumour was highly vascular, showing extensive areas of necrosis together with cellular areas traversed by fibrous tissue septa. The cells in these areas were suggestive of rather bizarre suprarenal cortical cells, a number of them showing a vacuolated eosinophilic appearance with small round nuclei, but others were more foamy in appearance and were suggestive of the cells found in a hypernephroma. Mitotic figures were not common (Fig. 476).
The hospital pathologist considered the appearances were not those of a phaochromocytoma, but more of an adrenal cortical carcinoma, or possibly of renal origin (Fig. 477).
The chromaffin reaction carried out by the method described by Carleton and Leach (1938, a) gave a negative reaction.
An attempt to demonstrate adrenaline histologically by the technique devised by Dr. W. Cramer (Carleton and Leach, 1938, b) proved unsuccessful, and negative results were obtained when the Vulpian reaction was carried out on an extract of the fresh tumour tissue prepared according to the method described by Hawk and others (1947).
The sections were subsequently examined by two Professors of Pathology, and both independently expressed the view that the structure of the tumour was that of an adrenal cortical carcinoma. One stated : “Compact clumps of cells in many parts and their vacuolated appearance closely resemble what are seen in the ordinary small cortical adenomas, and nowhere does the tumour show the diffuse pleomorphic-cell structure which is more characteristic of chromaffin tumours “.
DISCUSSION
Comprehensive reviews of adrenal cortical tu- mours have been made by Kepler and Keating (1941), Cahill, Melicow, and Darby (1942), Kenyon
d. Feminizing syndromes ;
e. Single or isolated endocrine manifestations (mentioned only by Kenyon) ; f. Non-hormonal tumours.
It is clear that our case does not fit into any of these groups, but the close correlation of many of
its features to those described as occurring in phæo- chromocytomata is remarkable, and has prompted us to publish this single case.
Duration of Symptoms .- In retrospect, it seems fair to assume that the symptoms experienced in 1942 were due to the tumour, particularly as during investigations prior to discharge from the Army in
1945 there was tenderness in the left hypochondrium, glycosuria, and the white-cell count was 10,200 per c.mm. Furthermore, at autopsy there was no evi- dence of past or present pericarditis-the diagnosis on which he was invalided out of the Forces.
A considerable number of cases of phæochromo- cytoma have been reported where it is certain that the tumour has been present for over ten years ; one of Bartels and Cattell’s (1950) cases first developed symptoms twenty-one years before being correctly diagnosed. Although some of the non-hormonal cortical tumours may well have been present for this length of time before diagnosis, most of the active cortical tumours have been diagnosed within a much shorter interval from the onset of the first symptom.
Pain .- Mild epigastric or retrosternal pain is common in the paroxysms of hypertension with phæochromocytomas. Severe pain, however, is a rarity in this condition, although Gilliland and Daniel (1951) report a case presenting as an ab- dominal emergency with excruciating abdominal pain radiating from the left flank. They suggest that hæmorrhage into the tumour is responsible for much of this symptom, and yet Lumb (1950) reports two enormous non-hormonal adrenal cortical tumours weighing 3750 g. and 5350 g. respectively, in which there was considerable hæmorrhage and necrosis but no pain. Non-hormonal cortical tumours, however, usually present with dull pain, presumably due to pressure on surrounding structures.
In our case there was considerable hæmorrhage into the tumour and it was also adherent to rib, aorta, and kidney, and all these factors were probably responsible for the intense, unusual, unrelievable pain which the patient experienced in his final exacerbation.
Paroxysmal Hypertension .- As pointed out by Bauer and Belt (1947), paroxysmal hypertension has been observed not only in phæochromocytoma but also in eclampsia, lead poisoning, essential hyper- tension, nephritis, aortitis, epilepsy, traumatic and vascular damage to the brain, meningitis, tabes, dis- eased Gasserian ganglion, sciatic neuritis, compres- sion of the vagus by tumour mass, typhoid and other acute infectious fevers, and even in a case allergic to Madeira wine. There is, however, no mention in this comprehensive list of suprarenal cortical tumours, but we find that Oppenheimer and Fishberg (1924) give references to 9 cases of hypertension in suprarenal cortical tumours, some of which could be regarded as paroxysmal. Plazy and Germain (1932) report a case of extensive aortic atheroma and aneurysm with bilateral suprarenal cortical tumours where there were two paroxysms of hypertension. Rimbaud and Delmas (1939) also describe a case of suprarenal cortical tumours in a man aged 57 with four paroxysms.
Paroxysmal hypertension has been reported with adrenal ganglioneuroma (Rogers, 1933) and with neuroblastoma (Ernould and Picard, 1934).
Demole and Rutishauser (1939) describe a par- ticularly interesting case of paroxysmal hypertension in a patient who ultimately proved to have tuber- culous destruction of the left adrenal gland. The fasting blood-sugar level was also variable in this case (100-170 mg. per cent), and transfusion of the
patient’s blood into a normal recipient produced an elevation of blood-pressure and blood-sugar level lasting for ten minutes.
McGavack, Benjamin, Speer, and Klotz (1942) report a case of malignant phæochromocytoma simu- lating a carcinoma of the adrenal cortex with second- ary adrenal insufficiency, and, in reviewing the pre- viously described malignant cases, point out that paroxysmal hypertension does not occur in malignant phæochromocytomas. Cross and Pace’s (1950) case, however, proved an exception.
Of special interest in our case was the rise to 260/170 under thiopentone, nitrous oxide, and oxygen anæsthesia. The reading was taken before cysto- scopy was undertaken and there was no suggestion of anoxia at the time.
It seems fairly clear that the mechanism of paroxysmal hypertension in phæochromocytoma is the release of adrenaline and noradrenaline. The effect of these substances on the human circulation has been studied by Goldenberg and others (1948) and Swan (1949). The exact cause of paroxysmal hypertension in conditions other than phæochromo- cytoma is a matter for speculation. In some cases it may be due to secondary adrenal medullary stimu- lation with the release of adrenaline substances, but it seems probable that in others, and perhaps in our case, invasion of, or pressure upon, the sympathetic nerve-plexuses and chain may have been a factor. Other pressor substances may be involved.
Excessive Sweating .- This was a marked feature in our case and is commonly found in cases of phæochromocytoma. It has not been observed as a special feature in cortical tumours.
Variable Fasting Blood-sugar is a very useful pointer to the diagnosis of phæochromocytoma, and a number of cases present as diabetes. Goldner (1947) reports a case where the diabetes cleared up after removal of the tumour.
A similar case is also reported by Duncan, Semans, and Howard (1944). Hyperglycemia is commonly associated with Cushing’s syndrome, but tends to be a constant finding rather than variable, as in our case.
Leucocytosis is also a common finding in phæo- chromocytoma, and was present in our case, varying from 10,000 to 18,000 per c.mm. It may, of course, be seen wherever a tumour is present and undergoing necrosis, but is not so commonly found in adrenal cortical tumours as in phæochromocytomas.
Sexual Changes .- One of the most outstanding features of our case is that there were no sexual changes, either in sexual activity or secondary sexual characteristics. We have not found any report of cortical tumours which can be regarded as hormon- ally active, without such changes. The adreno- genital syndrome and Cushing’s syndrome, or a mixture of these, are relatively common ; the feminiz- ing syndromes are much rarer. Armstrong and Simpson (1948) describe a case, and review only 8 previously reported cases.
The Histamine and Piperoxane Diagnostic Tests .- Bartels and Cattell (1950) review the various diagnostic tests for phæochromocytoma and point out, contrary to some earlier writers, that a negative histamine test does not exclude the condition. How- ever, it does appear to have been positive in the
ADRENAL CANCER SIMULATING PHAOCHROMOCYTOMA 403
majority of cases, and our negative result considerably disturbed our confidence in the pre-operative diag- nosis. It is of interest that the test should have been negative with a cortical tumour producing paroxysmal hypertension, when it is so frequently positive with medullary tumours.
The piperoxane test was unlikely to be of much value, as the resting blood-pressure was low at the time that the test was carried out.
Cause of Death .- The difficulties of controlling the blood-pressure during operations on phao- chromocytomas, and the likelihood of post-operative shock after removal of any form of adrenal tumour are well known, and described in detail by many of the above-mentioned authors. The curious way in which there was a progressive rise of the diastolic pressure with a stationary systolic pressure through- out the operation was another very unusual feature about our case. The pulse pressure at the start was only 40 mm. Hg, and for a considerable time before death was only 10 mm. These figures, together with the complete lack of response to piperoxane, also suggest that adrenaline was not the cause of the hypertension.
In conclusion, we can say that, even after a careful reconsideration of the clinical features, the diagnosis of phæochromocytoma was well justified. It is inter- esting to note that in spite of the size of the tumour, and a diligent search for it on clinical examination, it could not be palpated, nor did it produce any recognizable abnormality in the retrograde pyelo- gram. The fact that the tumour turned out to be a cortical carcinoma explains some of the anomalous findings, but makes it an even more unusual and fascinating clinical study, and leaves a number of problems unsolved. It is an aphorism that we diagnose what we know, and we hope that the above review of the extremely variable features of supra- renal tumours may help others, as it has helped us, to appreciate the possibility of these diseases when they present themselves in their various guises.
SUMMARY
I. A case is described of a man, aged 33 years, presenting many features of a phæochromocytoma, including paroxysmal hypertension, a variable hyper- glycæmia, and leucocytosis.
2. Excruciating pain was the most significant symptom.
3. Symptoms had been present for nine years, and he had previously been diagnosed as a ’ recurring pericarditis ‘.
4. At laparotomy a left suprarenal tumour was found and removed. Histologically, this appeared to be a suprarenal cortical carcinoma, and small second- ary deposits were found throughout the lungs. There was no evidence of pericarditis or renal damage.
5. Death occurred during operation, following a progressive rise of the diastolic blood-pressure, which finally approximated to the systolic pressure.
6. The main features of this unusual case are discussed in relation to previous cases found in the literature.
We wish to express our thanks to Mr. L. R. Broster for his advice and encouragement ; to Mr. M. Silverstone for permission to publish his opera- tive findings ; and to Dr. H. Maclean for the pathological data.
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