ACKNOWLEDGMENT

Mr. Roy for Statistical Analysis.

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1. Rodriguez-Galindo C, Wilson MW, Haik BG, et al. Treatment of

metastatic retinoblastoma. Ophthalmology 2003;110:1237–1240.

2. Chan HS, CantonMD, Gallie BL. Chemosensitivity and multidrug

resistant to antineoplastic drugs in retinoblastoma cell lines.

Anticancer Res 1989;9:469–474.

3. Chan HS, Thorner PS, Haddad G, et al. Multidrug-resistant

phenotype in retinoblastoma correlates with P-glycoprotein

expression. Ophthalmology 1991;98:1425–1431.

4. Chan HS, Lu Y, Grogan TM, et al. Multidrug resistance protein

(MRP) expression in retinoblastoma correlates with the rare failure

of chemotherapy despite cyclosporine for reversal of P-glycopro-

tein. Cancer Res 1997;57:2325–2330.

5. Krishnakumar S, Mallikarjuna K, Desai N, et al. Multidrug re-

sistant proteins: P-glycoprotein and lung resistance protein expres-

sion in retinoblastoma. Br J Ophthalmol 2004;88:1521–1526.

6. Johnson SW, Ferry KV, Hamilton TC. Recent insights into

platinum drug resistance in cancer. Drug Resist Updates 1998;1:

243–254.

7. Wernyj RP, Morin PJ. Molecular mechanisms of platinum

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containing chemotherapy in testicular germ cell tumors is

associated with downregulation of the protein kinase SRPK1.

Neoplasia 2004;6:297–301.

11. Abramson DH, Lawrence SD, Beaverson KL, Lee TC,

Rollins IS, Dunkel IJ. Systemic carboplatin for retinoblastoma:

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Abramson DH. New retinoblastoma tumor formation in children

initially treated with systemic carboplatin. Ophthalmology

2003;110:1989–1994.

13. Dorrell MI, Aguilar E, Weber C, Friedlander M. Global gene

expression analysis of the developing postnatal mouse retina.

Invest Ophthalmol Vis Sci 2004;45:1009–1019.

14. MohanA,KandalamM,RamkumarHL,Gopal L,Krishnakumar S.

Stem cell markers: ABCG2 and MCM2 expression in retinoblas-

toma. Br J Ophthalmol 2006;90:889–893.

Juxtaglomerular Cell Tumor in an 8-Year-Old Girl

Lei Shao, MD,1* Michelle Manalang, MD,2 and Linda Cooley, MD3

INTRODUCTION

Juxtaglomerular cell tumor (JGCT) is a rare renal neoplasm

mostly seen in patients in their 20s and 30s. It arises from the cells of

the juxtaglomerular apparatus. The tumor cells contain protogra-

nules of renin in the cytoplasm. Over 81 cases of JGCT have been

reported in the English literature, but only 3 occurred in children of

10 years of age or younger [1–3]. JGCT is benignwith the exception

of one case that showed pulmonary metastasis 6 years after

nephrectomy [4]. Clinically, almost all patients with JGCT present

with severe hypertension, hyperaldosteronism with hypokalemia,

elevated serum renin level, and a single tumor mass in the kidney.

Histologically, the tumor is variably cellular with thick-walled

blood vessels and sheets of oval to spindle cells.With ultrastructural

analysis, the cells contain rhomboid-shaped renin protogranules.

Despite its characteristic histopathologic, immunohistochemical,

and ultrastructural features, very little is known about its cytogenetic

characteristics.

CASE REPORT

The patient was an 8-year-old African-American female who

presented to the emergency department (ED) with a severe

headache. She had a 3-month history of worsening headaches

which occurred about twice aweek andwere accompanied by blurry

Juxtaglomerular cell tumor (JGCT) is an extremely rare renalneoplasm in the pediatric population. It is considered a benign tumorarising from the juxtaglomerular apparatus of the kidney. JGCT hascharacteristic clinicopathologic features, but its cytogenetic featuresare unknown. We report a case of JGCT in an 8-year-old female whopresented with severe hypertension, elevated serum renin level, and

a well circumscribed tumor in the right kidney. Protogranules ofrenin was identified in the cytoplasm of the tumor cells by electronmicroscopic examination. Fluorescence in situ hybridization re-vealed monosomy of chromosomes X, 6, 9, 11, 15, and 21. PediatrBlood Cancer 2008;50:406–409. � 2006 Wiley-Liss, Inc.

Key words: chromosome; cytogenetics; hypertension; juxtaglomerular cell tumor; renin

——————1Department of Pathology, Children’s Mercy Hospitals and Clinics,

School of Medicine, University of Missouri-Kansas City, Kansas City,

Missouri; 2Department of Hematology and Oncology, Children’s

Mercy Hospitals and Clinics, School of Medicine, University of

Missouri-Kansas City, Kansas City, Missouri; 3Section of Medical

Genetics, Children’s Mercy Hospitals and Clinics, School of Medicine,

University of Missouri-Kansas City, Kansas City, Missouri

*Correspondence to: Lei Shao, Department of Pathology, Children’s

Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108.

Received 25 April 2006; Accepted 31 July 2006

� 2006 Wiley-Liss, Inc.DOI 10.1002/pbc.21048

406 Brief Reports

vision. On admission to the ED, her blood pressure was 185/138.

She was transferred to pediatric intensive care unit for management

of her hypertension. She was placed on sodium nitroprusside drip,

which was slowly weaned after the addition of enalaprilat, 8 mg/kg/dose IVevery 8 hr and labetalol continuous infusion at 1.5mg/kg/hr.

Laboratory data were significant for a potassium of 3.0 mmol/L

(reference: 3.5–5.2 mmol/L), serum renin level of 20788 ng/dL

(reference for 5- to 9-year-old: 3–39.5 ng/dL), and a normal

aldosterone of 27 ng/dL. Echocardiography demonstrated concen-

tric left ventricular hypertrophy with near mid-cavity obliteration at

end systole. Renal ultrasound with renal Doppler showed a

hyperechoic right renal mass measuring 4.2� 3.6� 5.3 cm, with a

tiny anechoic area within the lesion. There was normal flow within

the main renal arteries and veins bilaterally. CT of abdomen and

pelvis revealed an exophytic, well defined mass in the lateral

aspect of the right kidney, measuring 4.7� 3.9� 5.5 cm. The tumor

had no significant mass effect upon the renal sinus, but appeared to

distend Gerota’s fascia or extend into the perinephric space.

Precontrast images suggested some internal hemorrhage or calci-

fication along the periphery. Therewas no adrenal, liver, or posterior

body wall invasion. Chest CT was negative for any intrathoracic

metastases.

A right radical nephrectomy with exploration of the left kidney

and periaortic lymph node biopsy was performed. The patient was

discharged 6 days after her surgery with enalapril and amlodipine as

antihypertensive medications. Amlodipine and enalapril were

discontinued 1 month after the surgery. Renin levels normalized

after surgery. Clinical follow-up of the patient at 6 and 18 months

after the surgery were unremarkable.

Pathologic examination revealed a well circumscribed, solitary

tumor of 5.0� 4.5� 4.0 cm in the lateral aspect of the kidney. The

tumor had variegated cut surfaces with small cystic areas of up to

0.7 cm in diameter. The tumor did not involve the renal pelvis.

Microscopically, under low-power magnification, the tumor had a

fibrous capsule and a vague nodular appearance due to variable

cellularity. Nodules of closely packed tumor cells were separated by

fibrous septa. Some areas of the tumor had myxoid and microcystic

changes (Fig. 1A). The tumor cells were polygonal or short spindle-

shaped with a moderate amount of eosinophilic cytoplasm and

indistinct cell borders (Fig. 1B). Branching tubular structures lined

by bland cuboidal epithelium were present within the tumor. Some

of the tubular structures were cystically dilated and filled

with eosinophilic material. Thick-walled arterioles with intimal

fibrosis and hyperplasia of the media were present and they focally

formed loose clusters in the tumor. Mitoses were not found. Mild

nuclear atypia was focally present in the tumor. The tumor was

confined to the kidney with no invasion into the renal sinus or renal

vessels. Rare arterioles in the adjacent kidney parenchyma showed

focal intimal fibrosis. The tumor cells were diffusely positive for

CD34, vimentin, and focally positive for actin (Fig. 1C). Ki-67

stained less than 1% of the tumor cells. The tumor cells were

negative for cytokeratin, EMA, CD31, and synaptophysin. CD117

stained individual or loosely clustered cells in the tumor. TheCD117

positive cells were also positive for tryptase consistent with mast

cells. The mast cells were variable in number from different areas

within the tumor. Theyweremore prominent in the hypocellular and

perivascular regions. The tumor cells were negative for CD117 and

tryptase.

Pediatr Blood Cancer DOI 10.1002/pbc

Fig. 1. Histopathologic features of juxtaglomerular cell tumor. A: Juxtaglomerular cell tumor with focal microcystic changes and thick-walled

arterioles.B: Sheets of polygonal tumor cellswith round nuclei, eosinophilic cytoplasm, and indistinct cell borders.C: Some tumor cells are positive

for smooth muscle actin. The smooth muscle cells of a thick-walled artery are also positive.D: Electron microscopy of juxtaglomerular cell tumor

with characteristic cytoplasmicmembrane bound rhomboid-shaped and round protogranules. [Color figure can be viewed in the online issue, which

is available at www.interscience.wiley.com.]

Brief Reports 407

Electron microscopic (EM) examination revealed membrane-

bound rhomboid crystals with a paracrystalline substructure in the

region of the Golgi apparatus. Round membrane-bound electron

dense granules were also present in the cytoplasm. The crystals and

granules corresponded to protogranules and secretory granules of

renin (Fig. 1D) and they are diagnostic of JGCT.

Three-color interphase fluorescence in situ hybridization (FISH)

were performed on touch preparations taken from frozen tumor

tissue using commercially available DNA probes (Vysis, Inc.,

Abbott Laboratories SA, Downers Grove, IL) (Table I). Six

hybridizations were performed each using three different fluoro-

chrome-labeled DNA probes. Two hundred non-overlapping, intact

nuclei were scored for each hybridization by two observers. A single

signalwas found for chromosomesX, 6, 9, 11, 15, and 21 in 80–90%

of the nuclei examined. Two signals were present for chromosomes

1, 3, 4, 7, 8, 10, 12, 13, 17, 18, and 20 in over 80% of the nuclei

examined. The presence of four signals was identified in a minority

of nuclei (less than 5%) examined. This suggests either a small

tetraploid or dividing (G2) population. The probe for chromosome

16was inconclusive showing 29%of nucleiwith one signal and 69%

with two signals.

DISCUSSION

JGCT was first described by Robertson et al in 1967 [5].

Since then, over 81 cases have been reported in the English literature

[5–13]. JGCT occurs in young adults with a mean age of 26.8

(range 6–69). There was a slight female predominance with a F/M

ratio of 1.8:1. Clinically, patients may experience headache,

dizziness, polyuria, and nocturia. Virtually all the patients with

JGCT had hypertension due to renin production in the tumor cells.

The hypertension and hypokalemia caused by elevated renin levels

in patientswith JGCTresolved spontaneously after surgical removal

of the tumor inmost of the reported cases, as in our case.Most JGCT

are small, well circumscribed, cortical masses and less than 4 cm in

diameter. Rarely, JGCT are 8 or 9 cm in diameter, but with no

vascular or sinus involvement. Three cases of JGCTwere reported in

children at 10 years of age or younger. The youngest child with

JGCTwas a 6-year-old girl [2] and the other two cases occurred in a

boy and a girl of 10 years of age. All three children had symptoms

and signs of hypertension. The serum renin levels were at least eight

times of the normal up reference values. The tumors measured 0.2,

0.8, and 2.3 cm in the greatest dimensions.

Histologically, JGCTare composed of polygonal to short spindle

cells with variable amounts of eosinophilic cytoplasm and indistinct

cytoplasmic membranes. Entrapped renal tubules and thick-walled

blood vessels are common findings of this tumor. Mild cytologic

atypia andmicroscopic foci of necrosis have been described in some

cases [8] and were not associated with adverse clinical prognosis.

Immunohistochemically, the tumor cells are diffusely positive

for vimentin, CD34 and focally positive for smooth muscle actin

[8–12]. It has been reported recently that tumor cells fromfive cases

of JGCTwere focally immunoreactive for CD117 [12]. In our case,

the focally positive CD117 cells were also positive for tryptase. The

immunophenotype and the morphology of these cells were most

consistent with mast cells. The tumor cells were negative for

CD117.Abundantmast cellswere observed in a previous case report

[9]. The diagnostic value of CD117 in JGCT should be validated

with proper controls of mast cell markers. Ultrastructurally,

membrane-bound rhomboid crystals and electron-dense secretory

granules are considered pathognomonic for JGCT.

The diagnosis of JGCT is usually made postoperatively after

total nephrectomy. Nephron-sparing surgery has been reported

Pediatr Blood Cancer DOI 10.1002/pbc

TABLE I. FISH Results With Different Probes

Hybridization Probes used Probe locus

Results per 200 nuclei scored

One signal Two signals Four signals

1 RB1 13q14 190 10

D17Z1 17cen 190 10

D21S259/341/342 21q22.13-22.2 182 8þ 10a

2 Sat II/III 1 1q12 193 7

D15Z1 15p11.2 181 12þ 7a

D16Z3 16q11.2 58 138 6

3 D7Z1 7cen 192 8

Alpha-sat 9 9cen 173 19þ 8a

Alpha-sat 10 10cen 192 8

4 Alpha-sat 4 4cen 188 12

D8Z2 8cen 188 12

D12Z3 12cen 188 12

5 DXZ1 Xcen 162 29þ 9a

D11Z1 11cen 162 29þ 9a

D20S108 20q12 191 9

6 D3Z1 3cen 200

D6Z1 6cen 191 9

D18Z1 18cen 200

The probes used and the actual scored results for each probe. Six hybridizations, each with three different

probes hybridized and scored simultaneously, show nuclei with one signal for chromosomes X, 6, 9, 11, 15,

and 21 in>80%of the nuclei examined. These same chromosomes show two signals, except chromosome 6,

while other probes show four signals.aTwo signals for these probes in the presence of four signals for the other simultaneously tested probes; cen,

centromere.

408 Brief Reports

[10,13]. JGCT is considered benign with total or partial nephrec-

tomy as the treatment. One case of malignant JGCT has been report

in a 52-year-old patient who had pulmonary metastasis 6 years after

the total nephrectomy [4]. The tumor measured 15 cm in greatest

dimension and was the biggest of all reported tumors. It also had

unfavorable histologic features such as necrosis, brisk mitotic

figures, and vascular invasion in the renal vein and inferior vena cava

in the primary tumor.

A single study of two JGCT using cytogenetic analysis, com-

parative genomic hybridization, and interphase FISH found gains of

chromosomes 10 and 20 with no chromosome losses in one tumor

and gains of chromosomes 4 and 10 with losses of chromosomes X,

9 and 11q in the second tumor [14]. Loss of chromosomes X, 9 and

11 were observed to our patient’s tumor and the number 2 tumor

reported byBrandal et al. Further, studies of other JGCTs are needed

to clarify the genetic makeup of this rare tumor.

REFERENCES

1. More IA, Jackson AM, MacSween RN. Renin-secreting tumor

associated with hypertension. Cancer 1974;34:2093–2102.

2. Hirose M, Arakawa K, Kikuchi M, et al. Primary reninism

with renal hamartomatous alteration. JAMA 1974;230:1288–

1292.

3. Kodet R, TaylorM, Vachalova H, et al. Juxtaglomerular cell tumor.

An immunohistochemical, electron-microscopic, and in situ

hybridization study. Am J Surg Pathol 1994;18:837–842.

4. Duan X, Bruneval P, Hammadeh R, et al. Metastatic juxtaglomer-

ular cell tumor in a 52-year-old man. Am J Surg Pathol 2004;28:

1098–1102.

5. Roberson PW, Klidjian A, harding LK, et al. Hypertension due

to a renin-secretion renal tumor. Am J Med 1967;43:963–976.

6. McVicar M, Carman C, Chandra M, et al. Hypertension secondary

to renin-secreting juxtaglomerular cell tumor: Case report and

review of 38 cases. Pediatr Nephrol 1993;7:404–412.

7. Abbi RK, McVicar M, Teichberg S, et al. Pathologic characteriza-

tion of a renin-secreting juxtaglomerular cell tumor in a child and

review of the pediatric literature. Pediatr Pathol 1993;13:443–451.

8. Martin SA, Mynderse LA, Lager DJ, et al. Juxtaglomerular cell

tumor: A clinicopathologic study of four cases and review of the

literature. Am J Clin Pathol 2001;116:854–863.

9. Ng SB, Tan PH, Chuah KL, et al. A case of juxtaglomerular cell

tumor associated with membranous glomerulonephritis. Ann

Diagn Pathol 2003;7:314–320.

10. Chambo JL, Falci JR, Lucon AM. Juxtaglomerular cell tumor as a

rare cause of hypertension in adults. Int Braz J Urol 2004;30:119–

120.

11. Kuten A, Olumi A, Goldsmith J, et al. Pathologic quiz case. A

symptomatic renal tumor. Juxtaglomerular cell tumor. Arch Pathol

Lab Med 2004;128:112–114.

12. Kim HJ, Kim CH, Choi YJ, et al. Juxtaglomerular cell tumor

of kidney with CD34 and CD117 immunoreactivity: Report of

5 cases. Arch Pathol Lab Med 2006;130:707–711.

13. Mete JK, Niranjan J, Kusum J, et al. Reninoma treated with

nephron-sparing surgery. Urology 2003;61:1259.

14. Brandal P, Busund LT, Heim S. Chromosome abnormalities in

juxtaglomerular cell tumors. Cancer 2005;104:504–510.

Prolactinoma as the First Manifestation of Gardner’s Syndrome

Geoffrey S. Goodin, MD,1 M. Beth McCarville, MD,1,5 Stephen N. Thibodeau, PhD,2

Stephen X. Skapek, MD,3,6 Joseph D. Khoury, MD,4,7 and Sheri L. Spunt, MD3,6*

Familial adenomatous polyposis (FAP) is a genetic disorder

caused by germline mutation of the APC (adenomatous polyposis

coli) gene on chromosome band 5q21 [1,2]. Affected patients

develop colonic adenomatous polyps early in life and have a nearly

100% lifetime risk of colorectal carcinoma. Gardner’s syndrome is

considered to be a variant of FAP with prominent extracolonic

Familial adenomatous polyposis (FAP) is an inherited conditioncausing numerous adenomatous colorectal polyps and a markedlyelevated risk of colon cancer. FAP may be associated with variousextracolonic manifestations such as desmoid fibromatosis andosteomas (termed Gardner’s syndrome) and brain tumors, usuallymedulloblastoma or glioma [termed Brain Tumor Polyposis (BTP)syndrome type 2]. We describe a pediatric patient who initially

presented with prolactinoma and later was found to have Gardner’ssyndrome. A germline mutation of the APC (adenomatous polyposiscoli) gene was identified. Our case illustrates the associationbetween prolactinoma and FAP, which may represent a rare subtypeof Gardner’s and BTP syndromes. Pediatr Blood Cancer2008;50:409–412. � 2006 Wiley-Liss, Inc.

Key words: desmoid tumor; familial adenomatous polyposis; Gardner’s syndrome; pituitary adenoma; prolactinoma

——————Grant sponsor: Cancer Center Support (CORE) Grant; Grant number:

P30 CA 21765; Grant sponsor: Cancer Center Grant; Grant number:

CA 23099; Grant sponsor: American Lebanese Syrian Associated

Charities (ALSAC).

*Correspondence to: Sheri L. Spunt, Department of Hematology-

Oncology, MS 260, St. Jude Children’s Research Hospital, 332 North

Lauderdale Street, Memphis, TN 38105-2794.

E-mail: sheri.spunt@stjude.org

Received 18 April 2006; Accepted 21 June 2006

——————1Department of Radiological Sciences, St. Jude Children’s Research

Hospital, Memphis, Tennessee; 2Department of Laboratory Medicine

and Pathology, Mayo Clinic College of Medicine, Rochester,

Minnesota; 3Department of Hematology-Oncology, St. Jude

Children’s Research Hospital, Memphis, Tennessee; 4Department of

Pathology, St. Jude Children’s Research Hospital, Memphis,

Tennessee; 5Department of Radiology, The University of Tennessee

College of Medicine, Memphis, Tennessee; 6Department of Pediatrics,

The University of Tennessee College of Medicine, Memphis,

Tennessee; 7Department of Pathology, The University of Tennessee

College of Medicine, Memphis, Tennessee

� 2006 Wiley-Liss, Inc.DOI 10.1002/pbc.20985

Brief Reports 409