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doi:10.1016/j.pr

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Pathology – Research and Practice 200 (2005) 857–860

www.elsevier.de/prp

TEACHING CASE

Renal variant of Anderson-Fabry disease and bilateral

renal cell carcinoma

Julia Blancoa,�, Jose Herrerob, Luis F. Ariasa,1, Noemı Garcia-Mirallesa,Carmen Gamezb, Alberto Barrientosb

aDepartment of Pathology, Hospital Clınico San Carlos, C/ Martin Lagos s/n, 28040 Madrid, SpainbDepartment of Nephrology, Hospital Clınico San Carlos, Madrid, Spain

Abstract

Anderson-Fabry disease (AFd) is an X-linked metabolic disease with clinical manifestations secondary toaccumulation of glycosphingolipids in various tissues. We report the first case in which a patient with renal variant ofAFd and chronic renal failure developed bilateral conventional renal cell carcinoma. His metabolic disorder wasdiagnosed only after histopathologic study of the kidney specimen resected because of the tumoral lesion. There is noclear etiologic relation between the metabolic and neoplastic disease. As AFd is not common or well known and itsclinical manifestations tend to be nonspecific, the disorder is often unrecognized, misdiagnosed, or diagnosed late inlife. The pathologist should be aware of this disorder when evaluating a kidney specimen from patients with chronicrenal failure of unknown cause.r 2004 Elsevier GmbH. All rights reserved.

Keywords: Fabry disease; Kidney failure; Metabolic disease; Renal cell carcinoma

Introduction

Anderson-Fabry disease (AFd) is a rare X-linkedlysosomal storage disorder caused by deficient activityof the lysosomal enzyme a-Galactosidase A (a-Gal A).This deficiency results in a progressive lysosomalaccumulation of GSLs (mainly globotriaosylceramideand galabiosylceramide) derived primarily from theturnover of cells in the kidneys, liver, lungs, anderythrocytes [2,7]. The genetic defect occurs in all celltypes, but involvement differs greatly among differentorgans, likely reflecting rates of sphingolipid metabolism[1]. In classically affected males, clinical manifestationsresult predominantly from the progressive lysosomal

e front matter r 2004 Elsevier GmbH. All rights reserved.

p.2004.09.003

ng author. Tel.: +34913303016; fax: +34 913303032.

ss: mblanco.hcsc@salud.madrid.org (J. Blanco).

s supported by University of Antioquia, Medellin,

deposition of GSLs in the vascular endothelium and, toa lesser extent, in other cell types [2]. The major clinicalmanifestations in hemizygous males include skin lesions(angiokeratomas), hypohidrosis, crises of severe pain inthe extremities (acroparesthesias), corneal and lenticularopacities, cardiac involvement, cerebrovascular mani-festations, and renal dysfunction [2,3]. An associationbetween AFd and neoplasms has not been previouslyaddressed in the literature. We report on a patient withend-stage renal disease (ESRD) caused by AFd, whichdeveloped bilateral renal clear cell carcinoma. Histologicevaluation of the kidney specimen played a crucial rolein the definitive diagnosis.

Case report

In June 1997, a 69-year-old man was admitted to thehospital because of chronic renal failure of unknown

ARTICLE IN PRESSJ. Blanco et al. / Pathology – Research and Practice 200 (2005) 857–860858

cause. His serum creatinine level was 4.2mg/dL,hemoglobin 10mg/dL, and uric acid 9mg/dL. Urinalysisrevealed amorphous crystals and proteinuria: 0.69 g/24 h; hematuria was absent. Blood analysis did notreveal immunologic alterations. His history was relevantfor hyperuricemia, gouty arthropathy, alcoholic chronichepatopathy without descompensation, and highblood pressure. Sonography showed a solid mass inthe upper pole of the left kidney, measuring2.7� 2.0� 2.0 cm. Ultrasound-guided needle aspirationwas performed, and cytologic evaluation showed a clearcell renal carcinoma. Computed tomography (CT) andsonography disclosed no expansive lesions in the rightkidney.The patient underwent radical nephrectomy. The

specimen revealed a single solid mass. Histologicexamination confirmed the cytologic diagnosis, and itwas classified as Fuhrman grade 2 and stage I (T1a, N0,M0) according to the TNM staging criteria. In addition,the glomeruli showed hypertrophic podocytes distendedwith foamy-appearing vacuoles, mesangial widening,and scarring. Vacuolation was also present in thecapillary endothelium and distal tubular epithelial cells,and less commonly in proximal tubules. Extensivedeposits were seen in arterial and arteriolar endotheliumand vascular smooth muscle cells. Electron microscopydemonstrated enlarged lysosomes with lamellated inclu-sions (myeloid or zebra bodies), confirming the diag-nosis of AFd (Fig. 1).After nephrectomy, the renal failure worsened, and

the patient began to undergo hemodialytic treatment. Inthe following year, right bundle branch block, leftventricular hypertrophy, and chronic obstructivebronchopathy appeared. In 1998, he underwent resec-tion of cataracts (there was no cornea verticillata). Arigorous examination demonstrated scant skin lesionsconsistent with spider nevus in the lower back.Angiokeratomas or other features typical of AFd, suchas neuropathic pain and decreased sweating, were notfound. Activity of a-Gal A in serum was less than 5% ofnormal data. Genetic study demonstrated mutationF113L (or Phe 113Leu) in exon 2, a substitution ofthymidine for guanine in codon 113, replacing pheny-lalanine with leucine.In July 2000, a new sonography revealed a right

kidney mass measuring 12 cm, occupying almost theentire organ. Nephrectomy was performed, and thehistologic study showed a clear cell renal conventionalcarcinoma, Fuhrman grade 3 and stage IV (T4, N2, M1)with perinephric extension and perihepatic peritonealinfiltration. Histologic features of AFd, as described inthe left kidney, were found in the right non-neoplastickidney. The patient continued on dialysis and, 5 monthslater, he presented progressive impairment of his generalcondition, right lumbar pain, and a palpable mass in thisregion. Numerous metastases were evidenced in lungs,

abdominal cavity, and liver. The patient died withextensive metastatic disease several months later.The patient was neither exposed to industrial chemi-

cals nor did he frequently take analgetics, and he had noobesity or chronic pyelonephritis, known risk factors forrenal carcinoma. The only risk factor was smoking: hehad smoked for 10 years until the left kidney carcinomawas diagnosed.In his family, enzymatic determination identified one

brother with a-Gal A activity (5.7%) and left ventricularhypertrophy with proteinuria: 0.2 g/24 h and normalkidney function: creatinine clearance: 118ml/min. Onesister had left ventricular hypertrophy and a-Gal Aactivity (27%). In two nephews, aged 22 and 24 years,5.7% and 5.9% a-Gal A activity was found; signs ofAFd (dermatologic, renal, or cardiac) were not noted,and there is no history of renal cancer in the patient’srelatives.

Discussion

To the best of our knowledge, an association betweenrenal cell carcinoma and AFd has not been reportedpreviously. It is not possible to determine the exactrelation. The Xq22.1 region, where the a-Gal A gene islocalized, is not known to be related to oncogenes ortumor suppressor genes. A review of the literature hasshown that neoplasms in AFd do not develop morefrequently, which might suggest a lack of a pathogenicrelation. In addition, in AFd, there is no prominentinflammatory or proliferative cellular response inkidneys. The patient had smoked for 10 years until hisleft tumor was diagnosed, and this is a risk factor forrenal cancer; however, renal carcinoma in smokers isuncommon. There might be an association of thebilateral renal cancer with AFd. However, with onlyone case, it must be assumed that the occurrence of renalcell carcinoma and AFd is purely coincidental.The right kidney neoplasm found 3 years after the left

kidney nephrectomy suggests a bilateral origin of theneoplasms, but is not possible to determine it exactly,because a metastatic origin of the carcinoma in thecontralateral kidney cannot be excluded. Even so, thereare factors speaking against a metastatic origin of theright mass: CT and sonography, done at the time of theinitial diagnosis of malignancy, did not demonstratetumoral lesions in the right kidney, nor did they revealthe low stage of the left carcinoma.In the present case, AFd was diagnosed on the basis

of histologic and ultrastructural examinations of renaltissue at the moment when the left mass was resected. Itis well known that AFd has clinical variants and aspectrum of clinical presentations. Hemizygous andheterozygous patients may remain asymptomatic during

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Fig. 1. (A) Left nephrectomy, a mass measuring 2.7 cm is shown in the middle zone of the kidney. (B) Glomerulus showing extensive

cytoplasmic vacuolation of podocytes and mesangial widening. Masson’s trichromic, 400� . (C) Tissue pretreated with osmium to

preserve the glycosphingolipid deposits and stained with fast green, showing extensive inclusion bodies of glycolipid in podocytes

and relative sparing of proximal tubules, 400� . (D) Deposition of glycolipid in endothelial cells of an artery is evidenced for the

extensive vacuolation. Masson’s trichromic, 400� . (E) (Inset) Electron microscopy of a glomerulus demonstrates a mixture of

lamellated structures in cytoplasm of podocytes, 6000� .

J. Blanco et al. / Pathology – Research and Practice 200 (2005) 857–860 859

most of their life, without any evident clinical sign ofAFd. Atypical clinical variants may have residualactivity of a-Gal A [3,5,8].The clinical history of our patient is compatible with

the renal variant of AFd. The ventricular hypertrophyhas been described as a component of this clinical variant[3,5]. The extensive glycosphingolipid deposition in therenal vascular endothelium supports this diagnosis. In thecardiac variant, renal biopsies reveal little, if any,endothelial glycosphingolipid deposition, and there isnormal renal function at ages well beyond those at whichclassically affected males develop renal insufficiency [6].The missense mutation F113L, found in our patient, hasbeen described in the cardiac variant of AFd [4], but thisdisorder is known to have phenotypic variability inpatients with the same genotype. Patients with the classicphenotype essentially have no a-Gal A activity; even so,as in the classic phenotype, some patients with renalvariant might have very low plasm a-Gal A activity [3,5].Atypical variants and the classical type of AFd consitutea spectrum of the disorder.

The clues as to the diagnosis are derived mainly fromrecognition of the associated extrarenal manifestations;therefore, patients without any evident extrarenal signshould not be diagnosed. Moreover, most of the renal-related symptoms and signs are nonspecific. In thepresent patient, extrarenal manifestations were detectedonly because of previous histologic examination. Someauthors agree that AFd should be considered as a causeof unexplained end-stage renal failure [3,5]. Our caseand others [5] indicate that the renal variant of AFd maybe underdiagnosed among renal dialysis and/or trans-plant patients, and it highlights the importance of arigorous examination of renal tissue on specimensresected for any reason.In conclusion, this case report documents an unusual

association between a renal variant of AFd and bilateralrenal cell carcinoma. It is not possible to determine ifthis association is more than casual. This case alsoemphasizes the importance of considering rare disordersin ESRD without any known cause and the relevance ofan exhaustive histopathologic examination in any case.

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