Fatal vertebral giant cell artertis

DiscussionGiant cell arteritis is a relatively common dis-ease in the elderly' and can affect almost allthe large arteries, including the aorta.34 Thesuperficial temporal and ophthalmic arteriesare often affected, causing headache andvisual disturbance. Polymyalgia rheumaticafrequently accompanies these symptoms. Theintracranial arteries are rarely affected,34 butthis has been reported in some cases.' 5The pathogenesis is unknown.34 Fragmen-

tation of the internal elastic lamina, aninflammatory infiltrate of mixed mononuclearand polymorphonuclear leucocytes, andcharacteristic multinucleated giant cells arethe histological hallmarks of the disease.4Immunological mechanisms have been postu-lated but the precise pathogenic processeshave not been elucidated.' Survival rates forGCA are similar to those of an age matchedpopulation,' and fatal complications in welltreated patients are rare, even in those withchronic relapsing disease.2 Early mortality(within six weeks of presentation)' whileuncommon, is usually associated with arteritisand brain stem infarction, or coronary arteri-tis and myocardial infarction.' 2 Late mortality(more than six weeks after presentation) dueto cerebral infarction is very rare.2 Death hasbeen attributed to insufficient corticosteroidtreatment.' In fatal cases due to vertebro-

basilar disease, necropsy showed either intra-cranial and extracranial arteritis with throm-bosis' or extracranial vertebral arteritis, withunaffected intracranial vessels.'Our case is the only one in which dissec-

tion of the intracranial portion of the verte-bral artery due to GCA is recorded, althoughdissection of the aorta has been documentedbefore.' It is not clear whether our patienthad continuous active arteritis or a relapsefollowing reduction of her maintenance treat-ment. It is clear, however, that severe GCAwith fatal complications occurred with a nor-mal ESR, without recurrence of initial symp-toms, and in spite of eight months ofcontinuous treatment. This case also showsthat active GCA may cause microscopic ver-tebral artery dissection.

1 Save-Soderbergh J, Malmvall BE, Anderson R, BengtssonB. Giant cell arteritis as a cause of death. JAMA 1986;255:493-6.

2 Graham E, Holland A, Avery A, Ross Russel RW.Prognosis in giant cell arteritis. Br Med Jf 1981;282:269-71.

3 Fauci AS, Haynes BF, Katz P. The spectrum of vasculitis;clinical, pathologic, immunologic and therapeutic con-siderations. Ann Intern Med 1978;89(part 1):660-76.

4 Graham DI. Vascular disorders of the central nervoussystem. In: Adams JH, Duchen LW, eds. Greenfield'sneuropathology. 5th edn. London: Edward Arnold, 1992:228-9.

5 Collado A, Santamaria J, Ribalta T, Cinta Cid M,Ca-Nete JD, Tolosa E. Giant cell arteritis presentingwith ipsilateral hemiplegia and lateral medullary syn-drome. Eur Neurol 1989;29:266-8.

J Clin Pathol 1993;46:1131-1133

Renal failure caused by leukaemic infiltration inchronic lymphocytic leukaemia

J K Phillips, P S Bass, G Majumdar, D R Davies, N F Jones, T C Pearson

St Thomas's Hospital,Lambeth Palace Road,London SEI 7EHDepartment ofHaematologyJ K PhillipsG MajumdarT C PearsonDepartment ofPathologyP S BassD R DaviesCorrespondence to:Dr J K PhillipsAccepted for publication1 July 1993

AbstractA case of B-CLL which was complicatedby chronic renal failure due to leukaemicinfiltration of the kidney is reported.Treatment with chlorambucil, pred-nisolone, and renal bed irradiationresulted in a substantial improvement inrenal function which persisted until thethe patient's death from marrow failuresome eight years later. The temporalassociation between treatments andresponse suggested that renal bed radio-therapy had contributed to the improve-ment in renal function. This case is one

of only two reported cases in whichchronic renal failure due to CLL hasbeen treated with radiotherapy. It isunique in that the renal response was

shown histologically.Leukaemic infiltration of the kidney is

common in CLL but, characteristically,is not associated with renal impairment.An improvement in renal fimction has

been described in two patients with acuterenal failure after chemotherapy.

(3 Clin Pathol 1993;46:1 131-1133)

Case reportA 60 year old man presented with generalisedlymphadenopathy without other abnormalphysical signs. Investigation showed the fol-lowing: haemoglobin 152 g/l; white cell count11-3 x 109A/ (lymphocytes 6-8 x 109/1); andplatelet count 120 x 109/1. The peripheralblood film showed a lymphocytosis with occa-sional "smudge" cells. Peripheral blood lym-phocyte surface markers were consistent withB cell CLL (91% positive for HLA-DR, 81%positive for CD19, 91% positive for CD5, 9%positive for CD2, 5% weakly positive forSmIg, 0-5% positive for FMC7, 1% positivefor CD10, 3% positive for CD25). A bonemarrow aspirate showed that 65% of nucle-ated cells were small lymphocytes. A bone

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marrow trephine biopsy specimen showedboth nodular and diffuse infiltration patterns.A chest x ray picture showed mediastinal lym-phadenopathy. Histological examination of acervical lymph node biopsy specimen showedreplacement of the normal architecture with a

diffuse, well differentiated lymphocytic infil-trate staining positively for surface and cyto-plasmic IgM and surface X light chain. At thistime the serum urea, creatinine, electrolytes,calcium, uric acid and immunoglobulin con-centrations were normal and no paraproteinwas found. B-CLL was diagnosed, but notreatment was given as the patient felt well.The patient remained well despite a rising

lymphocyte count for 12 months. He thencomplained of lethargy, a change in his senseof taste, and urinary frequency with frothy,smoky urine. He had lost 8 kg in weight over

the preceding three weeks. Examinationshowed generalised lymphadenopathy with-out splenomegaly, mild hypertension (bloodpressure 150/100 mm Hg) and grade IIhypertensive retinopathy. Investigation showed:haemoglobin 106 g/l; white cell count 90-5 x109/1 (lymphocytes 81-5 x 109/1); a plateletcount of 153 x 109/1; urea of 27-8 mmol/l;creatinine of 563,umol; creatinine clearance15 ml/minute; and a urinary protein excretionof 0-7 g/day. Serum calcium and uric acidvalues remained normal. Moderate glycosuriawas noted on urinalysis in the presence of aplasma glucose concentration of 4-8 mmol/l.A renal ultrasound scan showed normal sizedkidneys with no evidence of obstructivenephropathy; the only abnormality on plaintomography was the presence of slightly irreg-ular renal outlines. A needle renal biopsyspecimen showed severe tubular atrophy withwide separation of tubules by interstitial con-nective tissue heavily infiltrated by small lym-phocytes exhibiting the same surface markerpattern as the peripheral blood lymphocytes.The infiltrate was more pronounced in thecortex than in the medulla. Twenty nine of33 glomeruli showed ischaemic collapse withperiglomerular fibrosis, the remainder show-ing global sclerosis. The arteries showedmoderate fibroelastic intimal proliferationand mild hyaline arteriolar sclerosis waspresent (fig 1). These appearances wereinterpreted as showing severe ischaemicnephrosclerosis with infiltration of the corticalinterstitium by CLL.The patient received oral chlorambucil 20

mg daily for two days with oral Allopurinol200 mg daily. Treatment for renal failureconsisted of a low protein diet and oral bicar-bonate. Atenolol 50 mg daily was given forthe hypertension. Three weeks later the lym-phocyte count had fallen to 61 x 109/1 butthere had been a substantial decline in renalfunction with urea reaching 31-9 mmol/l andcreatinine 1124 ,umol/l. Further oral treat-ment with chlorambucil 20 mg once a day forthree days and prednisolone 20 mg threetimes a day for 10 days was given in additionto low dose renal bed irradiation (400 cGy intwo fractions given on successive days). Overthe next two weeks the serum creatinineconcentration fell to 496,umol/l and the ureato 17-9 mmol/l. This was followed by a fallin the lymphocyte count to 14 x 109/1 at aboutfive weeks after the second course of chemo-therapy. Figure 2 shows the changes in serumcreatinine and lymphocyte count in relationto treatment during this period.

Treatment for CLL was continued withmonthly courses of chlorambucil for a total ofnine courses. One month after completingchemotherapy the patient was asymptomatic,with lymphadenopathy confined to two smallcervical nodes. The lymphocyte count wasnormal at 2-6 x 109/1 and renal function hadshown further slight improvement with aserum creatinine of 362 pmol/l and urea of16-1 mmol/l. Renal biopsy was repeated fivemonths after radiotherapy and this showeda pronounced reduction in the extent of

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Renalfailure caused by leukaemic infiltration in chronic lymphocytic leukaemia

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cortical lymphocytic infiltration, althoughischaemic nephrosclerotic changes remainedunchanged (fig 3).

Subsequently the patient received intermit-tent treatment with oral chiorambucil with orwithout prednisolone whenever there was evi-dence of disease progression. Renal functionremained stable until he died, eight yearslater, of septicaemia secondary to bone mar-row failure associated with extensive marrowinfiltration by CLL.

DiscussionNecropsy studies report a prevalence of renalinfiltration in CLL of between 63% and90%.' 3 The histological appearance of infil-tration of the kidney by CLL has beendescribed in two previous publications. Acase report describes foci of lymphocytesscattered irregularly throughout the kidney,more common in the cortex than themedulla.4 In a study of 42 cases Schwartzet al observed discrete lymphocytic foci in thecortical interstitium, particularly the sub-capsular cortex, and along the vasa recta atthe corticomedullary junction.2 In this studyleukaemic foci were associated with fibrosis,tubular atrophy, and glomerulosclerosis.

In our patient initial treatment with chlo-rambucil resulted in an improvement in theperipheral lymphocyte count but was accom-panied by a deterioration in renal functionwithout evidence of renal cause for this. Itwas unlikely to have been due to uric acidnephropathy as the serum uric acid wasnever significantly raised and chemotherapywas accompanied by prophylaxis withAllopurinol. Light chain nephropathy is alsounlikely as a paraprotein was not demon-strated in either plasma or urine. No evidenceof amyloid was seen on the renal biopsy spec-imen and the serum calcium concentrationremained normal. It has been suggested thatthe kidney may act as a sanctuary site for

leukaemic cells in response to treatmentwith chemotherapy which may explain ourfinding of worsening renal failure in the faceof otherwise responsive disease.5 This is con-sistent with the subsequent improvement inrenal function accompanied by documentedreduction in lymphocytic infiltration of thekidney.The improvement in renal function fol-

lowed treatment with a combination ofchlorambucil, prednisolone, and renal bedirradiation. This response is not likely to berelated to chlorambucil as previous exposureto this agent had been ineffective. Eitherprednisolone or radiotherapy might havebeen responsible, but it is clear from fig 2 thatthe renal function improved before there wasany evidence of an effect on peripheral lym-phocytes. A possible synergistic effect of localradiotherapy with chemotherapy cannot,however, be excluded.

Although renal infiltration by CLL iscommon, reports of impairment of renalfunction associated with such infiltration arerare.465 Acute renal failure responded to oralchlorambucil in one case7 and chronic renalfailure seemed to respond to combinationchemotherapy (cyclophosphamide, vincris-tine, and prednisolone) in another.6 Merrilland Jackson reported that renal bed irradia-tion (of unspecified dose) was effective in onepatient,4 but Saggi et al found renal radiother-apy (850 rads to one and 700 rads to theother kidney over three weeks), together withoral prednisolone and chlorambucil, to beineffective in their patient.8 In each of thesefour cases response was assessed on the basisof changes in renal function alone. Ourpatient is at present unique in that prolongedimprovement in chronic renal failure followedtreatment and was accompanied by a demon-strable reduction in lymphocytic infiltrationof the kidneys.Our case shows that when chronic renal

failure occurs in CLL, leukaemic infiltrationof the kidney should be considered as a possi-ble cause. Renal bed irradiation may then beeffective treatment, leading to improvementin renal function.

1 Kirshbaum JD, Preuss FS. Leukemia: A clinical andpathologic study of one hundred and twenty-three fatalcases in a series of 14,400 necropsies. Arch Intern Med1943;71:777-92.

2 Schwartz JB, Samsuddin AM. The effects of leukemicinfiltrates in various organs in chronic lymphocyticleukemia. Hum Pathol 1981;12:432-40.

3 Barcos M, Lane W, Gomez GA, Han T, Freeman A,Priesler H, Henderson E. An autopsy study of 1206acute and chronic leukemias. Cancer 1987;60:827-37.

4 Merrill D, Jackson H. The renal complications ofleukemia. N EnglJ Med 1943;228:271-6.

5 Lightwood R, Barrie H, Butler N. Observations on 100cases of leukaemia in childhood. Br Med J 1960;5175:747-52.

6 Pagniez DC, Fenaux P, Delvallez L, Dequiedt P, GosselinB, Tacquet A. Reversible renal failure due to specificinfiltration in chronic lymphocytic leukemia. Am J Med1988;85:579-80.

7 Tucker B, Brown AL, d'Ardenne AJ, Cattell WR.Reversible renal failure due to renal infiltration andassociated tubulointerstitial disease in chronic lympho-cytic leukaemia. Nephrol Dial Transplant 1990;5:616-8.

8 Saggi S, Calandri C, Muhlfelder T, Choi H, Kahn T, KajiD. Renal failure due to leukaemic infiltration in chroniclymphocytic leukaemia. Nephrol Dial Transplant 1990;5:1051-2.

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