SYSTEMIC CANDIDIASIS AND RENAL INVOLVEMENT

1414

We have obtained a few autoradiographs of tumour cells in regional-vein blood from patients with carcinoma. An example is shown in fig. 5. When autoradiographs are heavy it may be impossible to identify the nature of the subjacent cell. Even with relatively few silver grains in the emulsion developed, identification of single cells may be even more difficult than it normally is. A few samples were examined from patients with reticuloses. In four out of seven patients with Hodgkin’s disease, the proportion of labelled cells was within the range found in healthy people. In the other three, the proportion was between 1-8% and 3-2%. In all eight patients with chronic lymphocytic leukaemia the proportion of labelled cells was within the range found in healthy subjects. In the three patients with chronic myeloid leukaemia there were higher counts, ranging from 1-3 to 8-9%. One patient with lymphoblastaemia had a count of 9-6%, and one with a reticulum-cell sarcoma had a count of 21-6%.

340 mg. per 100 ml., and serum-potassium to mEq. per litre. Dialysis was carried out twice and this brought the blood-urea down on both occasions. On Sept. 20 the abdominal and tracheostomy wounds broke down, and these needed drainage and constant dressing. On Oct. 1, thrush was noticed in the mouth. Two days later the temperature rose from 100-5 to 103°F and the pulse-rate from 120 to 140 per minute; blood-pressure fell from 140/100 to 125/90 mm. Hg, and the blood-urea was 225 mg. per 100 ml. The white blood-cell count fell from 12,000 per c.mm. on Sept. 17 to 3000 on Oct. 3. Melama developed and the patient’s condition gradually deteriorated until her death on Oct. 9 with a blood-urea of 365 mg. per 100 ml.

urea rose to

Summary

technique for preparing autoradiographs onMillipore ’membranes has been used to demonstrate thymidine uptake by tumour cells in human blood. A

This work was carried out with the help of a generous grant from the British Empire Cancer Campaign. We are greatly indebted to Dr. B. 1. Lord for advice and assistance with autoradiography; to our technicians for their valuable help; and to Mr. K. Moreman of the Institute of Cancer Research, Royal Cancer Hospital, for the

photographs. REFERENCES

Amano, M., Messier, B., Leblond, C. P. (1959) J. Histochem. Cytochem. 7, 153 Harris, H. (1959) Biochem. J. 73, 362. Kuper, S. W. A., Bignall, J. R., Luckcock, E. D. (1961) Lancet, i, 852. Lesher, S., Fry, R. J., Kohn, H. I. (1961) Exp. Cell Res. 24, 334. Malmgren, R. A., Pruitt, J. C., Del Vecchio, P. R., Potter, J. F. (1958) J. nat. Cancer Inst. 20, 1203. Quastler, H. (1960) Ann. N.Y. Acad. Sci. 90, 580. — Sherman, F. G. (1959) Exp. Cell Res. 17, 420. Seal, S. H. (1959) Cancer, Philad. 12, 590.

SYSTEMIC CANDIDIASIS AND RENAL INVOLVEMENT THOMAS LEHNER Lond., F.D.S.

M.B.

FELLOW, DEPARTMENT OF MORBID ANATOMY, POSTGRADUATE MEDICAL SCHOOL, LONDON, W.12 *

NUFFIELD

9-8

Bacteriology Swabs taken between Sept. 10 and Oct. 1 from the mouth and tracheostomy, and the sputum showed progressively heavier growths of Candida albicans. A pure growth was also isolated from the abdominal pus. Blood-cultures and the urine were sterile, but unfortunately neither was examined during the nine days before death.

Necropsy The heart showed areas of recent pericarditis, and scattered throughout the myocardium were white abscesses, 1-3 mm. in diameter; the endocardium and valves were not affected. The kidneys weighed 80 and 96 g., and had the features of chronic pyelonephritis. There were scattered abscesses similar to those seen in the heart in the renal parenchyma. Both pelves and ureters examined.

were

patent and

not

affected. The brain

was

not

Microscopy The pericardium was invaded by yeast cells and pseudohyphaz of candida and there were scattered foci in the myocardium (fig. 1). Many lesions showed myocardial necrosis and some displayed mononuclear and polymorphonuclear reaction while others were apparently unaffected. The kidneys showed diffuse chronic pyelonephritis. Yeast cells and pseudohyphas were found in the tubules, glomeruli, and interstitial spaces, some with a leucocytic reaction and others without. Candida invaded the tongue epithelium superficially and the tongue musculature deeply. The adrenals, lungs, and thyroid gland showed focal lesions. The actual cause of death brought on by debility and the

disseminated candidiasis, of multiple antibiotics and hydrocortisone. The diagnosis was not made clinically; but candidal fungaemia probably set in six days before death, as manifested by the rise in temperature and pulse-rate, the fall was use

MUCOCUTANEOUS candidiasis, or thrush, is well docubut vascular dissemination of candida to visceral organs has been recognised only lately. In their comprehensive review of 95 patients with systemic candidiasis, Louria et al. (1962) described three groups in a diminishing order of frequency: (1) disseminated candidiasis ; (2) candidal endocarditis; and (3) candidal

mented ;

meningitis. The purpose of this communication is to report 2 further cases of systemic candidiasis and to draw attention to renal candidiasis. THE FIRST CASE

A coloured housewife, aged 41 years, was admitted in August, 1962, with anxmia which was thought to be due to menorrhagia from uterine fibroids. She also had a history of chronic pyelonephritis. On Sept. 6, 1962, hysterectomy and salpingooophorectomy were carried out, and next day she had an episode of respiratory failure and hypotension. A tracheostomy was performed, and the blood-pressure was maintained with metaraminol (’Aramine’) and hydrocortisone. She was also given penicillin and tetracycline, and later chloramphenicol. A day later the urinary output diminished to 50 ml., the blood* Present address: Department of Dental Medicine, Guy’s Hospital Medical School, London, S.E.1.

Fig. 1-Gross candidal invasion (Grocott. x 120.)

of

pericardium and myocardium.

1415

in blood-pressure, and the rise in blood-urea. In the preceding month, cultures from the various sites yielded an increasingly significant growth of C. albicans, and two days before dissemination the patient was found to have oral thrush. THE SECOND CASE

A

housewife, aged 68 years,

was

admitted

on

March 1, 1963,

with a longstanding history of essential hypertension, and hasmaturia for a month. On examination she looked well for her age. Her blood-pressure was 240/130 mm. Hg. Investigation showed an anaplastic squamous-cell carcinoma of the bladder. The gut was prepared for three days before the operation of cystectomy and ureterocolic anastomosis with neomycin and bacitracin. The operation was on March 25, and a heavy pure culture of C. albicans was grown from a colonic swab. The patient became jaundiced after the operation and this was attributed to halothane. Her blood-pressure fell to 120/80 mm. Hg; the pulse-rate was regular and rose to 120 per minute. There was no evidence of cardiac failure or infarction. Hydrocortisone, tetracycline, chloramphenicol, novobiocin, and erythromycin were administered at various times. The patient’s temperature remained normal, except on the day before death when it rose to 102°F. Blood-urea gradually rose from a normal level before the operation to 365 mg. per 100 ml. on April 4, and in the same period, the white blood-cell count rose from 6000 to 20,000 per c.mm. Two blood specimens taken on April 4 yielded pure cultures of C. albicans. The urine was unfortunately not cultured after the operation. The patient died on April 8.

Necropsy The kidneys weighed 280 g. and 260 g. and showed numerous white abscesses, measuring 1-3 mm. Both cortex and medulla were invaded and the papillas were necrosed. The renal pelves were moderately inflamed, but the ureters looked normal and patent. A swab taken from the kidney gave a heavy pure growth of C. albicans. The other viscera displayed no abnormality. Microscopy Sections of the kidneys showed extensive abscesses, with necrosis and an intense polymorphonuclear infiltration (fig. 2). Proliferating hyphae and yeast cells of candida were found in the abscesses, interstitial tissue, glomeruli, and tubules. There was considerable oedema, separation of tubules, and internal Candida was not found in the other organs. Toxic necrosis of the liver caused by halothane could not be ruled out. The gut had been efficiently sterilised preoperativelv, and

hydronephrosis.

Fig. 2-Acute pyelonephritic (Periodic-acid/Schiff. x 65.)

abscess with candida in the lesion.

this had presumably permitted superinfection by C. albicans. The fungus may have reached the kidneys, either directly from the colon by ascending the ureters, or through the bloodstream. Although it is impossible to be certain, the clinical, bacteriological, and pathological evidence supports vascular spread, probably during the operation. Discussion

Oral thrush is commonly seen in debilitated patients; Boggs et al. (1961) found it in 15 % of patients with neoplastic disease, and Lehner’s (1964) figure for patients in general medical wards is about 10%. Occasionally, however, vascular dissemination may take place. Since the clinical and pathological recognition of systemic candidiasis may not be obvious, fourteen necropsy cases with evidence of oropharyngeal candidiasis were examined. Sections from all the visceral organs stained with the periodic-acid Schiff method were examined, whether the fungus was found in routinely stained sections or not. Dissemination had taken place in only 1 case (the first case already described), though thrombosed blood-vessels with the fungus were often seen in the oropharynx and oesophagus (fig. 3). In the remaining 13 subjects mucosal invasion was seen in the mouth (7), pharynx (6), oesophagus (5), stomach (2), and larynx (3); 1 case also showed aspergillosis in the lungs and in the meninges. It is not clear why candida disseminates in some patients and not in others. Braude and Rock (1959) suggested the following clinical criteria for the diagnosis of systemic candidiasis: (1) history of continuous antibiotic treatment during the course of a protracted debilitating illness; and (2) rapid deterioration of the general condition with development of fever, shock, gastrointestinal bleeding, and " depressed sensorium ". Although the first feature was present in both the present cases, the second was seen fully only in the patient with disseminated candidiasis. Moreover, a striking feature in both patients was a demonstrable source of candida. Early diagnosis of systemic candidiasis is of great importance, since intravenous amphotericin B may prove lifesaving (Lewin 1963). In candidiasis of the alimentary tract, however, prophylaxis and treatment is best achieved with nystatin tablets (500,000 units) dissolved in the mouth 4-5 times daily for as long as is

Fig. 3-Thrombosed blood-vessel invaded by candida. (Grocott. x 165.)

1416

required. While

a persistently high concentration is the most commonly affected sites-the mouth, pharynx, and oesophagus-the drug, since it is not absorbed, also reaches the rest of the gut. There is mounting clinical and experimental evidence that the kidneys are the most susceptible organs in disseminated candidiasis. Out of 45 necropsies in published reports, 40 showed invasion of the kidneys, 26 of the heart, 20 of the liver, 9 of the spleen, and 14 (out of 30) of the brain. Furthermore, the blood-urea is commonly raised, and candida is often cultured from urine. Louria et al. (1960) suggested that candida evaded host-defence reaction by its confinement within the lumen of renal tubules. Subsequently, rupture of hyphoe into the interstitial tissue gave rise to renal abscesses. Sabesin (1962) thought that in his patient dissemination from the kidneys followed acute candidal pyelonephritis which had caused ursemia. This view gains support from the second case reported here, showing the stage of acute candidal pyelonephritis as yet without dissemination to other organs. Gresham and Burns (1960) also suggested that secondary dissemination of candida in animals may occur from a primary renal lesion. Thus, while the kidneys may be one of many organs affected primarily by blood-stream dissemination, they may also be the sole source of secondary

maintained

at

vascular dissemination. Hurley and Winner (1963) have drawn attention to the possibility that renal candidiasis may become chronic and lead to hydronephrosis in man. They have also shown convincingly in mice that intravenous injection of small doses of C. albicans produced lesions that were confined to the kidneys, and that these began as acute pyelonephritis and progressed to chronic pyelonephritis and hydronephrosis. In man, renal candidiasis may take three forms which probably represent different stages of the same disease: 1. Acute pyelonephritis, as shown in the second case. 2. Disseminated candidiasis which involves several organs including the kidneys, some showing acute pyelonephritis, and others the fungus with little inflammatory response. Most patients belong to this group; some have pre-existing renal deficiency (as shown in the first case), while in others uraemia may follow renal candidiasis. 3. Chronic pyelonephritis and hydronephrosis (Hurley and and Winner 1963).

METASTASISING ISLET-CELL TUMOUR OF THE PANCREAS ASSOCIATED WITH HYPOGLYCÆMIA AND CARCINOID SYNDROME

J.

VAN DER

SLUYS VEER

J. C. CHOUFOER

M.D. Leiden

M.D. Leiden

A.

QUERIDO

M.D. Amsterdam OF THE DEPARTMENT OF CLINICAL ENDOCRINOLOGY AND DISEASES OF METABOLISM, UNIVERSITY HOSPITAL, LEIDEN, THE NETHERLANDS

R. O.

VAN DER

HEUL

C. F. HOLLANDER

M.D. Leiden

M.D. Leiden

T. G.

VAN

RIJSSEL

M.D. Utrecht OF THE DEPARTMENT OF

PATHOLOGY, UNIVERSITY OF LEIDEN

Carcinoid tumours arising in bronchus, stomach, or pancreas, which derive from the foregut, often differ considerably from those in other locations (Williams and Sandler 1963). The carcinoid syndrome has occasionally been found in association with neoplasms that do not resemble carcinoid tumours (Dengler 1959, Williams and Azzopardi 1960, Peart et al. 1963). We report here the development of the carcinoid syndrome as well as typical hypoglycsemic attacks in a patient with an islet-cell carcinoma of the pancreas.

Case-report The patient, a man born in 1899, was first admitted to a mental hospital in April, 1957, on account of aggressive and irrational behaviour. For more than a year he had had attacks of dizziness, sweating, unsteadiness, and difficulty in thinking. The symptoms were most pronounced before breakfast and disappeared after a meal. Fasting blood-sugar values as low as 30 mg. per 100 ml. were reported. The patient was transferred to the department for clinical endocrinology and diseases of metabolism. No physical abnormality was found. When food was withheld for twelve hours the blood-sugar fell to 48 mg. per 100 ml. (Hagedorn-Jensen). Severe symptoms of hypoglycsemia made it necessary to administer glucose intravenously, which promptly relieved the symptoms. Organic hyperinsulinism was

tentatively diagnosed.

Renal candidiasis could perhaps be added as a fourth group to the classification of systemic candidiasis by Louria et al. (1962).

Summary

systemic candidiasis renal invasion was prominent. Microscopic examination of all the organs for fungal lesions in 14 necropsies on subjects with candidiasis of the upper digestive tract revealed dissemination in 1 only. In 2

I wish

cases

to

of

thank Prof. C. V. Harrison for

helpful advice

in the

preparation of this paper, and for permission to publish the records; Prof. R. Shackman" for permission to publish the clinical details of the two cases; and Mr. J. E. Hutchinson for the photomicrographs. REFERENCES

Boggs, D. R., Kearns, J. S., Williams, A. F., Howell, A., Jr. (1961) Arch. intern Med. 107, 354. Braude, A. J., Rock, J. A. (1959) ibid. 104, 107. Gresham, G. H., Burns, M. (1960) Progress in the Biological Sciences in Relation to Dermatolcgy; p. 174. London. Hurley, R., Winner, H. I. (1963) J. Path. Bact. 86, 75. Lehner, T. (1964) Oral Surg. (in the press). Lewin, K. (1963) Postgrad. med. J. 39, 359. Louria, D. B., Fallon, N., Brown, H. G. (1960) J. clin. Invest. 39, 1435. Stiff, D. P., Bennett, B. (1962) Medicine, 41, 307. Sabesin, S. M. (1962) Arch. intern. Med. 110, 526. —

Fig. 1-Malignant islet-cell tumour of pancreas: pancreatic tissue is seen in the right upper quadrant. (Haematoxylin and eosin. x 80.)