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Immunosuppression andIntracerebral Lymphomas

THE LANCET

THERE is mounting evidence to indicate that recipi-ents of renal transplants who are maintained onlong-term immunosuppressive therapy run an in-creased risk of malignant disease.1 The tumourswhich arise most commonly are lymphomas, andattention has been drawn to the disproportionatenumber of cases in which lymphomas were foundmainly or exclusively within the brain.2,3 A report 3from Denver, dealing with some 5000 recipients ofkidney grafts from all parts of the world, describes22 cases of lymphoma, in which 11 were intracerebral.More detailed analysis of the findings in these 11patients has disclosed a remarkable situation. Their

ages ranged from 14 to 52 years, with an average of29t years. The lymphoma was wholly intracerebralin 8 individuals, 1 patient had cerebral and pulmonaryinvolvement, 1 patient had tumour in the brain andcervical lymph-nodes, and 1 patient had intracerebrallymphoma and a Kaposi sarcoma of the skin. Apartfrom 2 " unclassified " lymphomas, the remaining 9tumours were described as reticulum-cell sarcomas.The organ donors were apparently free of malignantdisease at the time of grafting and only 1 of the

recipients in whom intracerebral lymphoma developedhad any neurological abnormalities before trans-

plantation. All patients received long-term immuno-suppressive treatment with azathioprine and pred-nisolone ; 3 were also given antilymphocyte globulin,and 5 underwent splenectomy. The interval betweentransplantation and the detection of cerebral tumoursvaried between 5i and 46 months, with an average ofabout 16 months. Once apparent, the neurologicalsymptoms progressed rapidly and 9 of the 11 patientsdied within a few weeks to several months after

diagnosis. The unusual features of these cases areself-evident. Involvement of the nervous system inwidely disseminated lymphomas is familiar enough,but lymphoma confined predominantly or exclu-sively to the brain is rare.4,5 No less striking is thelow age-incidence in these patients and the rapidclinical course of the malignant disease.Many questions arise. Were the tumours derived

from host or recipient tissues ? Origin from thedonor seems remote, since there was no evidencethat living neoplastic cells were inadvertently trans-

1. Lancet, 1969, i, 505.2. Penn, I., Starzl, T. Int. J. clin. Pharmacol. 1970, 3, 49.3. Schneck, S. A., Penn, I. Lancet, 1971, i, 983.4. Sparling, H. J., Jr., Adams, R. D., Parker, F., Jr. Medicine, Baltimore,

1947, 26, 285.5. Rosenberg, S. A., Diamond, H. D., Jaslowitz, B., Craver, L. F.

ibid. 1961, 40, 31.

planted with the homografts. If the tumours arosede novo in the recipients, was this the consequenceof chronic drug-induced immune deficiency ? It is

widely accepted that such an association exists, butwhat is the underlying mechanism ? Four main

hypotheses are proposed at present 3: sustained

antigenic stimulation by the homograft, direct

damage inflicted by the immunosuppressive agentsthemselves, depression of the normal immunologicalsurveillance mechanisms, and the proliferation ofoncogenic viruses. The last two hypotheses meritparticular attention. Evidence for depression ofimmunological surveillance, although largely cir-

cumstantial, is now extensive 6; while the particularattraction of oncogenic viruses in this context isthat they may act equally well on their own or, incompany with other agents, as co-carcinogens. 7There are several more specific questions. Why,

for instance, do lymphomas in chronicallyimmunosuppressed patients tend to be confined

predominantly or exclusively to the brain ? It hasbeen known for many years that homotransplantedand heterotransplanted tumours grow progressivelywhen inoculated intracerebrally,8 but SCHNECK andPENN 3 emphasise that the immunologically privi-leged conditions found in the brain are not invariable.Some antigens introduced intracerebrally may evokean immune reaction, and a secondary immuneresponse can be produced within the brain; it isnevertheless agreed that the brain (perhaps becauseit lacks a lymphatic system 9) reacts feebly to mostantigenic stimuli and it is likely that what little

capacity for immune response the normal brain mayhave is undermined by chronic immunosuppression.SCHNECK and PENN suggest that immune surveil-lance outside the brain may still be sufficient to

prevent the development of generalised lymphomas;within the brain, local conditions favour tumour

growth, so that lymphomas are more likely to beencountered inside the brain than outside it. But

why lymphomas rather than gliomas ? The argu-ments from Denver suggest that the tumours maybe derived from extracerebral malignant lymphoidcells (perhaps transformed by oncogenic virus),which then reach the brain in the bloodstream and

develop there because of the favourable intracerebralenvironment. It is perhaps surprising, if this is thecase, that such tumours have usually been singlerather than multiple; and a primary intracerebralorigin cannot be excluded. Reticulum cells are

present in the meninges and in the perivascularsheaths of perforating blood-vessels,10 and these arealternative candidates for the cell of origin. There is,however, a problem here, since the relation between

6. Burnet, F. M. Immunological Surveillance. Oxford, 1970.7. Roe, F. J. C., Rowson, K. E. K. Int. Rev. exp. Path. 1968, 6, 181.8. Greene, H. S. N. Ann. N.Y. Acad. Sci. 1957, 69, 818.9. Yoffey, J. M., Courtice, F. L. Lymphatics, Lymph and the Lympho-

myeloid Complex. New York, 1970.10. Russell, D. S., Marshall, A. H. E., Smith, F. B. Brain, 1948, 71, 1.

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cerebral reticulum cells and microglia is uncertain. 10, 11The arguments are abstruse, but the practicalimplication is clear enough: if these tumours doindeed arise intracerebrally, then assumptions abouttheir lymphomatous nature may have to be re-

examined.

Fatal Drug ReactionsCOMPARATIVELY few adverse reactions to drugs are

recorded in the medical journals or reported to bodiessuch as the Committee on Safety of Drugs.12 Inevit-

ably, therefore, the recognition of such reactions maybe delayed, and significant associations betweenclinical events and administration of a drug may behard to establish with any certainty. About 10%of drugs prescribed in the United Kingdom are forpatients in hospital, and it is clearly easier to monitoradverse reactions in these circumstances than in

outpatient or general practice. Through the BostonCollaborative Drug Surveillance Program, SHAPIRO etal.13 have carried out a prospective inquiry in six hos-pitals, one for the treatment of chronic diseases andfive general medical hospitals, covering 6199 patients.744 patients died in hospital and, of these, 27 (0-44%of the whole series) were judged to have died as aresult of drug treatment. This association hadbeen arrived at only after careful consideration of theclinical history by a clinical pharmacologist and theattending physician, and no case was included as a" drug death " unless both agreed that the drug ordrugs implicated were the most important or solefactors responsible for death.

Potassium supplements were implicated in 5 deathsout of 1949 patients given potassium; and SHAPIROet al. suggest that potassium chloride may be usedin some hospitals more often than is necessary.Intravenous infusions caused 4 deaths out of 2048

patients so treated, and SHAPIRO et al. emphasisethat, although the rapid administration of largevolumes of fluid is particularly dangerous in the

presence of cardiac failure, the risk of pulmonaryoedema is real even in the apparent absence of pre-disposing factors. Narcotic and sedative drugs,including chlorpromazine and chlordiazepoxide, wereincriminated in 3 deaths. Superinfection and

septicaemia accounted for the deaths of 3 patientsout of 2548 treated with antibiotics. 2 patients diedof massive internal hxmorrhage after intravenous

heparin therapy (361 patients had intravenous

heparin). Although digitalis intoxication is oftenmentioned as a major cause of drug-induced morbi-dity,14 only 1 death occurred out of 1254 patients at

11. Russell, D. S., Rubinstein, L. J. Pathology of Tumours of theNervous System. London, 1963.

12. Lancet, 1971, i, 1227.13. Shapiro, S., Slone, D., Lewis, G. P., Jick, H. J. Am. med. Ass.

1971, 216, 467.14. Chung, E. K. Digitalis Intoxication. Amsterdam, 1969.

risk. 2 deaths were attributed to dehydration andelectrolyte depletion out of 1254 patients treated withdiuretics. In both cases frusemide was among the

drugs used, and SHAPIRO et al. emphasise that power-ful diuretics should not be given without soundindications. Hypoglycxmia due to insulin was thecause of death in 2 out of 353 patients exposed, andsingle deaths were attributed to neostigmine, aspara-ginase, cyproterone acetate, adrenal steroids, and

diethylstilbcestrol. During the period of this

inquiry, 3-6% of hospital deaths were attributed todrug treatment, and although sometimes the severityof the disease was such that life may not have been

appreciably shortened as a result, in others the situa-tion was different. The message from these findingsis one that is surely applicable wherever powerfuldrugs are used: better education in the indicationsand hazards of treatment and constant vigilance inprescription and administration.

IgA DEFICIENCY AND COELIAC DISEASETHE commonest of the immunoglobulin deficiencies

selective for Ig class (dysgammaglobulinaemias) isa lack of IgA, which is either absent or wellshort of normal levels (125-425 mg. per 100 ml.)in about 1 in 500 of the general population 1-that is,with about six times the frequency of hypogamma-globulineemia spread over the Ig classes. A tendencyto clustering in families has been noted, suggesting apossible genetic basis. Although it may apparently besymptomless, isolated IgA deficiency is often associa-ted with sinopulmonary infections, which may reflectan accompanying local dearth in the respiratory tractof the IgA-producing plasma cells needed to providethe immunoglobulin protein component of secretoryIgA. Such infections are a well-recognised accompani-ment of the serum IgA deficiency found in 85% ofpatients with hereditary ataxia telangiectasia 2 an ill-understood association which it can only be concludedrepresents a coincidence of two independent geneticfactors.

Of wider clinical interest, though even less well

understood, are certain other relationships recentlydiscerned between IgA deficiency and various disorders.For example, although many patients with coeliacdisease have normal or even raised levels of serum

IgA,3 nevertheless on biopsy examination their jejunalmucosas show a loss of the normal preponderance ofIgA cells among the local plasma-cell population ofthe lamina propria, IgM cells predominating instead.This reversal of the normal state of affairs is echoedin the frequency of frank serum IgA deficiency, which,although unusual in coeliac disease, is about ten timescommoner in this condition than in the general popu-lation.4 An explanation of this discrepancy in coeliacdisease between the degree of IgA-cell depletion in

1. Hobbs, J. R. Lancet, 1968, i, 110.2. Petersen, R. D. A., Kelly, W. D., Good, R. A. ibid. 1964, i, 1189.3. Beale, A. J., Parish, W. E., Douglas, A. P., Hobbs, J. R. ibid. 1971,

i, 1198.4. Asquith, P., Thompson, R. A., Cooke, W. T. ibid. 1959, ii, 129.