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IDNEY BIOPSY TEACHING CASE

SLE: The Great Imitator Strikes Again

Jane M. Bell, MD, Ramesh Nair, MD, Agnes Solon, MD, and Patrick D. Walker, MD

NDEX WORDS: Systemic lupus erythematosus (SLE), renal cell carcinoma, renal biopsy, paraneoplastic syndrome.

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YSTEMIC LUPUS erythematosus (SLE) isan autoimmune disease that may involve

ultiple organ systems. Renal involvement maye indicated by isolated proteinuria or protein-ria and hematuria, possibly with an associatedecrease in renal function. In patients with symp-oms of renal involvement, renal biopsy typicallys performed to obtain histological classificationf the type of renal disease. This provides thera-eutic guidance and helpful prognostic informa-ion. We present a case in which the renal biopsyed to an unexpected diagnosis and a very inter-sting clinical course.

CASE REPORT

A 68-year-old African-American woman presented to herhysician with polyarthralgias, pleuritic chest pain, short-ess of breath, and decreased exercise tolerance. She alsoeported blurring of vision, a foreign-body sensation in herye, dry mouth, and lower-extremity and periorbital edema.

The patient’s medical history was remarkable for diabetesf greater than 20 years’ duration, hypertension, and arevious cerebrovascular accident. Family history was posi-ive for heart disease, hypertension, diabetes, sarcoidosis,nd polymyositis.

Physical examination showed blood pressure of 162/80m Hg; pulse rate, 80 beats/min; respirations, 20 breaths/in; and weight, 259 lbs. Periorbital edema was noted. Sheas afebrile and had no evidence of alopecia, skin rash,

ymphadenopathy, or organomegaly. Chest examinationhowed no friction rub.

Laboratory studies showed a positive antinuclear anti-ody titer at 1:1,280, with positive anti-double strandedNA (47 IU/mL; normal, �25 IU/mL) and antihistone

ntibody titers (4.6 IU/mL). Complete blood count showedypochromic microcytic anemia. Urinalysis results wereositive for blood and protein. A 24-hour urine collectionhowed protein of 6.76 g/24 h. Erythrocyte sedimentationate was 112 mm/h. Complement levels were normal.

A percutaneous renal biopsy was performed under com-uted tomographic guidance. No mass lesions were identi-ed at the time of biopsy.

idney BiopsyThe biopsy specimen consisted of 5 pieces of tissue

btained by needle biopsy varying from 0.2 to 0.5 cm inength that were submitted for examination by light micros-opy, immunofluorescence, and electron microscopy. Micro-copic examination showed that all submitted tissue con-isted of a proliferation of enlarged cells with clear cytoplasm

n an alveolar to focally tubular arrangement, showing a

merican Journal of Kidney Diseases, Vol 45, No 1 (January), 200

etwork of delicate thin-walled vascular channels. Nucleiere intermediate in size and round to slightly irregular,ith some showing prominent nucleoli. Ultrastructural ex-

mination showed the cells to contain clear cytoplasm withrominent lipid vacuoles and scattered glycogen granules.he diagnosis of renal cell carcinoma, clear cell type,uhrman grade 2 was made (Figs 1 and 2).

linical Follow-UpThe patient underwent a left nephrectomy 2 weeks after the

nitial biopsy. The nephrectomy specimen showed a 5.0 � 4.04.0 cm clear cell carcinoma involving the lower pole of the

idney. No capsular or vascular invasion was identified, andurgical margins were negative for tumor.

Non-neoplastic renal tissue showed diffuse and nodularlomerulosclerosis consistent with diabetic nephropathy, focallobal sclerosis, and severe arteriosclerosis (Figs 3 and 4).mmunofluorescence stains for immunoglobulin G, immuno-lobulin M, immunoglobulin A, C3, C4, C1q, albumin, fibrino-en, and � and � light chains were negative. Electron micro-copic examination showed thickened capillary loops andesangial matrix expansion with nodule formation. No electron-

ense deposits were identified.The patient reported improvement of her pleuritic chest

ain and arthralgias after surgical recovery. Follow-up labo-atory studies showed the disappearance of antinuclear andnti-double stranded DNA antibodies. At 1 year of follow-p, the patient had no evidence of recurrent or metastaticenal cell carcinoma and no evidence of SLE.

DISCUSSION

The existence and nature of a possible relation-hip between rheumatic disorders and malig-ancy have been proposed.1-7 Possibilities in-lude rheumatic syndromes as premalignantonditions with increased risk for the develop-ent of malignancy, the development of malig-

ancy secondary to cytotoxic therapy for rheu-atic disorders, and a paraneoplastic association

f a rheumatic disorder with a malignancy.

From Nephropathology Associates, Little Rock, AR.Received April 23, 2004; accepted in revised form May

4, 2004.Address reprint requests to Jane M. Bell, MD, Nephropathol-

gy Associates, 10802 Executive Center Dr, Ste 111, Bentonldg, Little Rock, AR 72211. E-mail: belljm@kidneybx.com© 2004 by the National Kidney Foundation, Inc.0272-6386/04/4501-0027$30.00/0

doi:10.1053/j.ajkd.2004.05.049

5: pp 219–222 219

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BELL ET AL220

The diagnosis of SLE was made in this patientased on fulfillment of the American Rheuma-ism Association criteria (presence of at least 4 of1 defined criteria): arthritis, renal disorder, pres-nce of antinuclear antibody, and presence ofnti-double stranded DNA antibody. She alsoad a history of pleuritic chest pain, although noriction rub was heard on examination. Based onhe significant proteinuria and presence of hema-uria, lupus nephritis was strongly suspected, andrenal biopsy was performed. The diagnosis of

enal cell carcinoma on the renal biopsy wasompletely unexpected given the clinical situa-ion and because no mass lesion was appreciatedt the time of the biopsy procedure.

The improvement in symptoms and disappear-nce of the antinuclear and anti-double strandedNA antibodies after resection of the renal cell

arcinoma suggests the possibility of a paraneo-lastic syndrome. Classification of any set oflinical abnormalities as a paraneoplastic syn-rome is based on 2 criteria: the syndrome mustppear after the onset of the malignancy, and

Fig 1. Clear cell carcinoma showing trabecular ar-hitecture and prominent vascular channels (periodiccid–Schiff; original magnification �200).

reatment of the malignancy must result in disap-pn

earance of paraneoplastic symptoms.8 In thisase, the development of signs and symptoms ofLE in close association with the discovery of aenal cell carcinoma, followed by the resolutionf symptoms and absence of autoantibodies afteresection of the tumor, indicate fulfillment ofoth requirements.Symptoms of a paraneoplastic syndrome not

elated to tumor mass or tumor invasion are seenn 10% of patients with cancer at the time ofnitial diagnosis, and up to 50% of patientsxperience a paraneoplastic syndrome at someoint during their course.7 Paraneoplastic rheu-atic syndromes are not uncommon. Hypertro-

hic osteoarthropathy, dermatomyositis/polymyo-itis, and paraneoplastic vasculitis are seen mostrequently. Subacute cutaneous lupus occasion-lly has been described as a paraneoplastic syn-rome associated with solid tumors, includingarcinoma of the lung,9-11 stomach,12 breast,13

iver,14 and uterus,15 as well as with hematologicalignancies.5 To the best of our knowledge,

nly 7 reports of SLE or lupus like syndromesccurring as paraneoplastic syndromes can be

Fig 2. Nuclei are intermediate in size with scattered

rominent nucleoli (periodic acid–Schiff; original mag-ification �400).

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SLE: THE GREAT IMITATOR STRIKES AGAIN 221

ound in the literature. The associated neoplasmsnclude ovarian adenocarcinoma,16 ovarian semi-oma,17 bronchioalveolar carcinoma,18 carci-oma of the breast (2 patients),19 alveolar softart sarcoma,20 epidermoid carcinoma of theung,21 and Castleman’s disease.22 The 2 patientsith carcinoma of the breast developed lupus

ike syndromes after receiving radiation therapyor advanced local disease, raising the possibilityhat tissue irradiation may have initiated an abnor-

al immunologic response that led to the lupusike syndrome. Although myopathy23 and anti-hospholipid antibody syndrome24,25 have beeneported as paraneoplastic syndromes associatedith renal cell carcinoma, this case represents

he first report of a paraneoplastic association ofLE with renal cell carcinoma.The absence of evidence of lupus nephritis in

he nephrectomy specimen requires reexamina-ion of the cause of the patient’s proteinuria andematuria. In areas away from the neoplasm, theidney showed classic features of diabetic ne-hropathy. Can this explain the laboratory test

Fig 3. Glomeruli from nephrectomy specimen show-ng well-formed mesangial nodules (periodic acid–chiff; original magnification �200).

esult alterations seen in this patient? Certainly,bS

roteinuria is common in patients with diabeticephropathy. However, hematuria, although per-aps less commonly considered a feature ofiabetic nephropathy, also is associated with dia-etic nephropathy in up to 30% of patients.26

nother possible explanation of the hematuria ishe presence of the renal cell carcinoma itselfecause hematuria is found in 50% to 60% ofatients with such a neoplasm.The occurrence of a neoplasm and the occur-

ence of SLE are both relatively common events,nd coincidental occurrence of the 2 in a patientertainly is possible. Although a search for annderlying malignancy is not indicated in everyatient with SLE, it is worthwhile to examineactors that might indicate that SLE or a similarheumatic/autoimmune process is associated withn underlying malignancy. This issue has beeniscussed in reviews of paraneoplastic rheumaticyndromes.1,7 Clinical findings found to corre-ate with the presence of an underlying malig-ancy include such epidemiologic consider-tions as history of malignancy or family historyf malignancy, exposure to carcinogens, late age

Fig 4. Glomerulus with thickened basement mem-

ranes and mesangial expansion (periodic acid–chiff; original magnification �400).

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t onset of rheumatic syndrome (�50 years),rominent constitutional symptoms (fever, mal-ise, and weight loss), and a poor response toonventional medical treatment. Only 1 of thesendings, age of onset older than 50 years, wasresent in our patient.To the best of our knowledge, this case repre-

ents the first report of a paraneoplastic associa-ion of SLE with renal cell carcinoma. It alsoerves as a reminder that rheumatic/autoimmuneyndromes, particularly when atypical in presen-ation, may herald the presence of an underlyingalignancy. Moreover, it is a warning that a

iopsy performed for medical renal disease mayhow an unexpected malignancy, even thougherformed under ultrasound or computed tomo-raphic guidance.

ACKNOWLEDGMENTThe authors thank Dr Stephen Bonsib for assistance and

upport and Denise Norwood for help with manuscriptreparation.

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