ACKNOWLEDGMENT
Mr. Roy for Statistical Analysis.
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metastatic retinoblastoma. Ophthalmology 2003;110:1237–1240.
2. Chan HS, CantonMD, Gallie BL. Chemosensitivity and multidrug
resistant to antineoplastic drugs in retinoblastoma cell lines.
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3. Chan HS, Thorner PS, Haddad G, et al. Multidrug-resistant
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5. Krishnakumar S, Mallikarjuna K, Desai N, et al. Multidrug re-
sistant proteins: P-glycoprotein and lung resistance protein expres-
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Rollins IS, Dunkel IJ. Systemic carboplatin for retinoblastoma:
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Stem cell markers: ABCG2 and MCM2 expression in retinoblas-
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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: [email protected]
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