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Recurring translocation (10;17) and deletion (14q) in clear cell sarcoma of the kidney.

* Context.--Clear cell sarcoma of the kidney (CCSK) is a prognostically unfavorable renal neoplasm of childhood. Previous cytogenetic studies of CCSK have reported balanced translocations t(10;17)(q22;p13) and t(10;17)(q11; p12). Although the tumor suppressor gene p53 is located at the chromosome 17p13 breakpoint, p53 abnormalities are rarely present in these tumors.

Objective.--To identify cytogenetic abnormalities in CCSK and correlate these findings with other clinicopathologic parameters.

Design.--A retrospective review of CCSK patients from 1990 to 2005 was conducted at our medical center. We performed clinical and histologic review, p53 immunohistochemical and classic cytogenetics (or ploidy analysis), and p53 fluorescence in situ hybridization analyses.

Results.--Five male patients (age range, 6 months to 4 years) were identified with cytogenetic abnormalities. Of 3 cytogenetically informative cases, one revealed a clonal balanced translocation t(10;17)(q22;p13) and an interstitial deletion of chromosome 14, del(14)(q24.1q31.1), and the other 2 patients had normal karyotypes. Fluorescence in situ hybridization for p53 in the t(10;17) case revealed no deletion. Immunohistochemical evaluation of p53 demonstrated lack of nuclear protein accumulation in all cases.

Conclusions.--Together with the published literature, our results indicate that translocation (10;17) and interstitial deletions of chromosome 14q are recurring cytogenetic lesions in CCSK. To date, 3 cases of CCSK or "sarcomatoid Wilms tumors" have been reported to exhibit t(10;17). One previously reported case of CCSK contained deletion 14q. Results of p53 immunohistochemistry and/or p53 fluorescence in situ hybridization in this report suggest lack of mutations or deletions of this tumor suppressor in these CCSK cases. The t(10;17) breakpoint and deletion of chromosome 14q24 suggest that other genes are involved in tumor pathogenesis.

(Arch Pathol Lab Med. 2007;131:446-451)


Clear cell sarcoma of the kidney (CCSK) is a pediatric renal tumor that affects children primarily between the ages of 2 and 5 and accounts for 3% to 5% of all childhood renal tumors. (1) Like anaplastic Wilms tumors and malignant rhabdoid tumors of the kidney, CCSK is classified as a tumor with unfavorable histology by the National Wilms Tumor Study Group because of its propensity to metastasize to bone and recur years after the original diagnosis. (2) The tendency of this tumor to develop bone metastases led Marsden and Lawler (3) to originally designate this tumor as "bone metastasizing renal tumor of childhood."

Clear cell sarcoma of the kidney is typically centered in the medulla and is characterized grossly by a fleshy tan, firm cut surface. Several histologic patterns are recognized, but the classic pattern is typified by nests and cords of cells separated by fine, arborizing fibrovascular septa (so-called chicken-wire pattern), and collagenous material intermingled among tumor cells. Nuclei are optically clear with fine chromatin, round to oval in shape, lack prominent nucleoli, and mitoses are generally infrequent. (4) Anaplastic features may be seen in rare cases of CCSK.

Unlike Wilms tumor, CCSK is not associated with any genetic syndromes and its molecular pathogenesis remains poorly understood. (2) Other renal tumors of childhood have been associated with recurring genetic abnormalities: deletion or mutations of WT1 and p53 in some Wilms tumors, t (12;15) creating the ETV6-NTRK3 fusion gene in congenital mesoblastic nephroma, and INI1 deletions or mutations in malignant rhabdoid tumors. (5-8) In addition, anaplastic Wilms tumor, classified by the National Wilms Tumor Study Group with CCSK and malignant rhabdoid tumors as having a prognostically unfavorable histology, has been shown to harbor p53 mutations. (9,10) Although Punnett et al (11) described a t(10;17) involving a breakpoint at the p53 locus chromosome 17p13, the majority of CCSK cases to date have been shown to lack p53 abnormalities, occurring only in tumors with anaplastic features. (12,13) Prior to the report of Punnett et al, Douglass et al (14) reported the tumor karyotype of a single case of CCSK with a complex karyotype that included deletion of chromosome 14q23. In this same report, a "sarcomatoid Wilms tumor" (likely CCSK, in present terminology) harbored a complex karyotype that included t(10;17)(q11; p12). Rakheja et al (15) later reported a CCSK in a 12-month-old boy with t(10;17)(q22;p13). More recently, Cutcliffe et al (16) have described activation of the sonic hedgehog and Akt signaling pathways in CCSK with up-regulation of neural markers. The same study suggests that CD117 and epidermal growth factor receptor may be potential therapeutic targets in some cases of CCSK.

Herein we describe the cytogenetic and/or ploidy analysis of 5 patients with CCSK, and correlate this with clinicopathologic and p53 immunohistochemical findings. Significantly, we identified a fourth patient with a clonal t(10; 17)(q22;p13), a finding that appears to be a nonrandom chromosomal abnormality in some patients with CCSK. In addition, we report the second occurrence of deletion (14)(q24.1q31.1) in this tumor.


Case Selection

The surgical pathology database of the Department of Pathology was searched after institutional approval to identify patients diagnosed with CCSK from 1990 to 2005. Information obtained documented histologic features, staging, and, in some cases, immunohistochemical findings. A search was also performed to identify the corresponding cytogenetics reports in the Clinical Cytogenetics Laboratory Section on Medical Genetics at the same institution.

Tumor Cell Culture and Cytogenetics

In 3 of 5 cases, fresh tumor tissue was obtained for cytogenetic analysis in a sterile manner in the operating room and placed into sterile RPMI tissue culture media supplemented with 15% (vol/vol) fetal calf serum. Tumor tissue was minced with scalpels and cultured in situ on coverslips using Amnio Max C100 supplemented with 15% (vol/vol) fetal calf serum and 1% penicillin-streptomycin (Invitrogen, Carlsbad, Calif). Cultures were incubated at 37[degrees]C with a 5% C[O.sub.2] atmosphere. Before harvesting, cells were treated with Colcemid (Invitrogen). The cells were subsequently harvested, treated with hypotonic saline solution, and fixed with methanol. Metaphase chromosomes were trypsinized and stained with Wright Giemsa stain (GTG method). A total of 20 metaphase spreads were analyzed for each of the examined cases.

Histology and Immunohistochemistry

All tissues were obtained from the surgical pathology laboratory at Wake Forest University Baptist Medical Center and fixed in 10% neutral-buffered formalin. Routine tissue processing was subsequently performed before paraffin embedding. Five-micrometer sections were cut with a microtome and stained with hematoxylin-eosin.

Additional unstained sections were deparaffinized, washed, and placed in phosphate-buffered saline, pH 7.4. Sections were subsequently treated using sodium citrate as an antigen unmasking reagent before washing in phosphate-buffered saline, pH 7.4, for 10 minutes. An aliquot of p53 monoclonal antibody (clone DO-7, dilution 1:50, Dako, Carpinteria, Calif) was added to each slide, followed by addition of a biotinylated goat anti-mouse antibody (1:100 dilution, Dako). The AEC chromogen (Ventana Medical Systems, Tucson, Ariz) was used to develop the slides.

Ploidy Analysis

A CAS 200 image analyzer (Cell Analysis, Inc, Evanston, III) was used to determine DNA content of Feulgen azure A-stained, 5-[micro]m thick, formalin-fixed, paraffin-embedded tissue sections per the manufacturer's recommendations.

Fluorescence In Situ Hybridization

A 10-[micro]L aliquot of p53 cDNA probe (Vysis, Inc, Downers Grove, III) was added to the slides for the case identified as having t(10;17)(q22;p13). The sections were denatured at 73[degrees]C for 5 minutes and hybridized for 2.5 hours at 37[degrees]C using a Hybrite (Vysis). They were subsequently washed and counterstained with DAPI (Vysis) following the manufacturer's recommendations. The slides were examined with an Olympus fluorescence microscope (Olympus America, Melville, NY) and images were captured using a Retiga digital camera (Q Imaging, Burnaby, British Columbia).


Clinicopathologic Findings

Five male patients with CCSK, ranging in age from 6 months to 4 years, were identified in our database (Table). As determined by National Wilms Tumor Study Group criteria, 2 patients were stage I, 2 patients were stage II, and one was stage IV with pulmonary and bony metastases (this patient died within 8 months of diagnosis). With the exception of the latter patient, all other patients are alive with no evidence of disease. Four patients presented with both hematuria and a flank mass, and one patient presented with flank mass alone. Three tumors were identified within the right kidney, and 2 were present in the left kidney. Grossly, these tumors were characterized as well demarcated, tan to tan-white, and firm (Figure 1, A). All but one case demonstrated at least focal areas of hemorrhage, necrosis, and cystic degeneration. Tumor size in greatest dimension ranged from 2.2 to 14 cm. Histologically, these cases were composed of round-to-polygonal cells with a high nuclear to cytoplasmic ratio (Figure 1, B through F). Nuclei were optically clear and vesicular. A fine capillary network and numerous mitotic figures were appreciated in all cases.


Cytogenetic and DNA Ploidy Analysis

Karyotypes were available for 3 cases (Table), and one case failed to grow in culture. However, DNA ploidy analysis was available for the case without a karyotype. Two cases had normal male karyotypes, and one case had a clonal abnormality 46,XY, t(10;17)(q22;p13), del(14) (q24.1q31.1) in 20 of 20 cells examined (Figure 2). At the time of diagnosis, the 2 patients with normal karyotypes were at stage I disease and the patient with the translocation and deletion was at stage II disease. The other patient with stage II disease had diploid DNA content, as did the patient with stage IV disease.


p53 Fluorescence In Situ Hybridization

Hybridization of metaphase chromosomes derived from patient 4 was examined after hybridization with a p53 DNA probe (Vysis) using fluorescence microscopy. All 20 metaphase spreads examined contained 2 copies of p53, one hybridization on the normal chromosome 17 and one on the derived chromosome 17 (Figure 3, A).


p53 Immunohistochemistry

Immunohistochemical staining for p53 was performed on paraffin-embedded tumor tissue in all cases, and compared with a control case of neuroendocrine carcinoma with known p53 mutation. All 5 cases of CCSK demonstrated less than 10% of cells with nuclear immunoreactivity (Figure 3, B).


The molecular pathogenesis of CCSK remains enigmatic, and cytogenetic studies have been reported for only a few cases. In 1989, Punnett et al (11) first reported a single case of CCSK that demonstrated a t(10;17)(q22;p13). Prior to this study, Douglass et al (14) reported a "sarcomatoid Wilms tumor" with a complex karyotype including t(10; 17)(q11;p12), and a single case of CCSK with chromosomal abnormalities including deletion of chromosome 14q23. There was no documentation of the histologic features for the latter tumor, and it is conceivable that this tumor was CCSK instead of a sarcomatous Wilms tumor. After 15 years, an additional case of CCSK containing t(10;17)(q22; p13) was reported by Rakheja et al, (15) a finding that bolstered the notion that this cytogenetic abnormality was a nonrandom finding in at least a subpopulation of patients with CCSK. In our study, t(10;17)(q22;p13) was identified in only 1 of 3 cases of CCSK for which Giemsa banded chromosomes were available. With this small number of cases and review of the few reports of t(10;17) in CCSK in the literature, the prognostic significance, if any, of this translocation is unknown. Cytogenetically normal karyotypes in CCSK are not unusual; however, 2 of 3 informative cases herein were karyotyped as 46,XY. This suggests that tumors that are cytogenetically normal may, for example, have mutations of gene(s) adjacent to the t(10;17) breakpoint or methylation-dependent inactivation of gene expression. Other reports of CCSK involving cytogenetic characterization have documented a variety of other chromosomal abnormalities, including loss of chromosome 11p and t(2;22)(q21;q11), the latter translocation suggesting a relationship with malignant rhabdoid tumors of the kidney. (17,18)

Given the unfavorable prognosis of CCSK and recurring translocations involving chromosome 17p13, the role of the p53 tumor suppressor in CCSK pathogenesis has been investigated through immunohistochemical, molecular, and functional assays. (12,13) Immunohistochemistry for p53 nuclear protein in CCSK has provided mixed results, with some cases showing no nuclear accumulation, and others showing more intense immunoreactivity suggestive of p53 mutations. Two of 3 CCSK cases with anaplasia, albeit extremely uncommon, contained strong p53 immunoreactivity, highly suggestive of p53 mutations, just as in anaplastic Wilms tumors. (1,19) In a previous report by this laboratory, the function of p53 in CCSK primary tumor cell cultures was intact, as evidenced by the expression of [p21.sup.WAF1] following DNA damage in primary tumor cell cultures. (13) In the present study, none of the CCSK cases demonstrated nuclear accumulation of p53 protein, a finding that is in accord with nonanaplastic tumors previously described in a larger series. (1) To determine if the p53 gene may have been lost as a result of the t(10;17) in patient 4, p53 fluorescence in situ hybridization was performed on metaphases from patient 4. This study consistently documented 2 signals indicating no loss of p53.

With the recurring observation of t(10;17)(q22;p13) in some cases of CCSK and the lack of documented p53 abnormalities in most CCSK cases as determined with immunohistochemistry, direct DNA sequencing, or functional analysis, it seems clear that other genetic mechanisms are responsible for the pathogenesis of this tumor. The t(10;17)(q22;p13) translocation breakpoint and del (14q24.1q31.1) may offer evidence of other candidate genes involved in CCSK pathogenesis. Abnormalities involving chromosome 10q22 has been reported in several other malignant solid tumors including uterine leiomyosarcoma, hepatocellular carcinoma, and endometrial adenocarcinoma. (20-22) In addition, a putative tumor suppressor and oncogene at chromosome locus 10q22 includes TET1 and LCX, both genes previously shown to form fusion gene products in acute myeloid leukemias. (23,24) At chromosome 17p13, several additional genes known to be involved in tumorigenesis should be considered. These include GAS7 (growth arrest-specific 7) gene, which has been shown to form fusion transcripts with the MLL gene in treatment-related acute myeloid leukemia. (25) Deletion of chromosome 14 extending from the q24 to q31 band encompasses additional candidate genes involved in tumorigenesis, including SEL1L (the human ortholog of the C elegans sel-1 suppressor enhancer of lin-12), CHES1 (checkpoint suppressor 1), and MAP3K9 (mitogen activated protein kinase kinase kinase 9) genes. SEL1L has been shown to suppress pancreatic adenocarcinoma and breast tumor cell growth in in vitro and in vivo assays, (26,27) and CHES1 is a checkpoint suppressor gene, which is reportedly underexpressed in oral squamous cell carcinomas. (28)

To date, only a small number of CCSK cases have been examined by cytogenetics, but the recurring finding of t(10;17) and del(14q24q31.1) underscores the importance of further examination of these abnormalities as they relate to CCSK pathogenesis. The t(10;17) and del(14q) case described herein will provide a resource to further characterize these genetic abnormalities through molecular biologic techniques. To understand what, if any, clinical (prognostic) significance this translocation has will require characterization of additional cases and correlation with patient outcomes.

We acknowledge the support of the Department of Pathology, Wake Forest University School of Medicine.


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(21.) Kim GJ, Cho SJ, Won NH, et al. Genomic imbalances in Korean hepatocellular carcinoma. Cancer Genet Cytogenet. 2003;142:129-133.

(22.) Sirchia SM, Sironi E, Grati FR, et al. Losses of heterozygosity in endometrial adenocarcinomas; positive correlation with histopathologic parameters. Cancer Genet Cytogenet. 2000;121:156-162.

(23.) Ono R, Taki T, Taketani T, Taniwaki M, Kobayashi H, Hayashi Y. LCX, leukemia-associated protein with CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23). Cancer Res. 2002; 62:4075-4080.

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(25.) Megonigal MD, Cheung NK, Rappaport EF, et al. Detection of leukemia-associated MLL-GAS7 translocation early during chemotherapy with DNA topoisomerase II inhibitors. Proc Natl Acad Sci U S A. 2000;97:2814-2819.

(26.) Orlandi R, Cattaneo M, Troglio F, et al. SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro. Cancer Res. 2002;62:567-574.

(27.) Cattaneo M, Orlandini S, Beghelli S, et al. SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo. Oncogene. 2003;22:6359-6368.

(28.) Chang JT, Wang HM, Chang KW, et al. Identification of differentially expressed genes in oral squamous cell carcinoma (OSCC): overexpression of NPM, CDK1 and NDRG1 and underexpression of CHES1. Int J Cancer. 2005;114:942-949.

Accepted for publication August 10, 2006.

From the Department of Pathology (Drs Brownlee, Perkins, Iskandar, and Garvin) and the Department of Pediatrics, Section on Medical Genetics (Mr Stewart, Ms Jackle, and Drs Pettenati and Koty),Wake Forest University School of Medicine, Winston-Salem, NC. Dr Brownlee is now with the Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Noel A. Brownlee, MD, PhD, Johns Hopkins University Hospital, Department of Pathology, Weinberg Building, Room 2242, 401 N Broadway, Baltimore, MD 21231 (e-mail:

Noel A. Brownlee, MD, PhD; L. Allen Perkins, MD; Will Stewart, BS, CLSpCG; Beth Jackle, BS, CLSpCG; Mark J. Pettenati, PhD; Patrick P. Koty, PhD; Samy S. Iskandar, MBBCh, PhD; A. Julian Garvin, MD, PhD
Clinicopathologic and Cytogenetic/Ploidy Data in 5 Cases of Clear
Cell Sarcoma of the Kidney *

Patient No. Age/Sex Anatomic Stage
 Site, Kidney

 1 3 y/M Left II
 2 3 y/M Right IV, bone and lung
 3 10 mo/M Left I
 4 6 mo/M Right II

 5 4 y/M Right I

Patient No. Patient Status p53 IHC Cytogenetics/Ploidy

 1 NED NR Diploid
 2 DOD NR 46,XY

 3 NED NR No metaphases
 4 NED NR 46,XY,t(10;17)
 5 NED NR 46,XY

* IHC indicates immunohistochemistry; NED, no evidence of disease;
NR, nonimmunoreactive; and DOD, died of disease.
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Author:Brownlee, Noel A.; Perkins, L. Allen; Stewart, Will; Jackle, Beth; Pettenati, Mark J.; Koty, Patrick
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Clinical report
Geographic Code:1USA
Date:Mar 1, 2007
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