Epidemiologic and Clinical Outcomes of Pediatric Renal Tumors in Korea: A Retrospective Analysis of The Korean Pediatric Hematology and Oncology Group (KPHOG) Data.

PURPOSE: Renal tumors account for approximately 7% of all childhood cancers. These include Wilms tumor (WT), clear cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor of the kidney (MRTK), renal cell carcinoma (RCC), congenital mesoblastic nephroma (CMN) and other rare tumors. We investigated the epidemiology of pediatric renal tumors in Korea. MATERIALS AND METHODS: From January 2001 to December 2015, data of pediatric patients (0-18 years) newly-diagnosed with renal tumors at 26 hospitals were retrospectively analyzed. RESULTS: Among 439 patients (male, 240), the most common tumor was WT (n=342, 77.9%), followed by RCC (n=36, 8.2%), CCSK (n=24, 5.5%), MRTK (n=16, 3.6%), CMN (n=12, 2.7%), and others (n=9, 2.1%). Median age at diagnosis was 27.1 months (range 0-225.5) and median follow-up duration was 88.5 months (range 0-211.6). Overall, 32 patients died, of whom 17, 11, 1, and 3 died of relapse, progressive disease, second malignant neoplasm, and treatment-related mortality. Five-year overall survival and event free survival were 97.2% and 84.8% in WT, 90.6% and 82.1% in RCC, 81.1% and 63.6% in CCSK, 60.3% and 56.2% in MRTK, and 100% and 91.7% in CMN, respectively (p < 0.001). CONCLUSION: The pediatric renal tumor types in Korea are similar to those previously reported in other countries. WT accounted for a large proportion and survival was excellent. Non-Wilms renal tumors included a variety of tumors and showed inferior outcome, especially MRTK. Further efforts are necessary to optimize the treatment and analyze the genetic characteristics of pediatric renal tumors in Korea.

Role of Cyclin D1 and BCOR Immunohistochemistry in Differentiating Clear Cell Sarcoma of Kidney From its Mimics.

BACKGROUND AND AIM: Clear cell sarcoma of kidney (CCSK) is the second most common pediatric renal malignancy, constituting ∼3% of renal tumors. Due to its morphologic diversity, the diagnosis of CCSK is often challenging. Recent studies have identified internal tandem duplication of BCL6 corepressor (BCOR) gene in CCSKs which coupled with cyclin D1 immunoreactivity, is helpful in differentiating it from its mimics, particularly blastema-rich Wilms tumor (WT), malignant rhabdoid tumor (MRT), and congenital mesoblastic nephroma (CMN). We aimed to evaluate the utility of cyclin D1 and BCOR immunohistochemistry in differentiating CCSK from its morphologic mimics. MATERIALS AND METHODS: Our cohort comprised of 38 pediatric renal tumors which included CCSK (n=18), WT (n=10), MRT (n=5), and CMN (n=5) cases. A detailed clinicopathologic analysis was performed, and tissue microarray were constructed for CCSK and WT, while MRT and CMN tumors were individually stained. RESULTS: The age ranged from 2 months to 16 years with male:female ratio of 3:1. Strong, diffuse nuclear immunoreactivity for cyclin D1 and BCOR was noted in 61% (n=11/18) and 83% (n=15/18) of CCSK, respectively, while it was significantly less in WT (n=3/10 for cyclin D1) (n=2/10 for BCOR). None of the MRT and CMN examples demonstrated any immunoreactivity. Interestingly, only the blastemal component of WTs showed distinct, rare nuclear immunoreactivity for cyclin D1 or BCOR and the combination of these was never positive in a given case. CONCLUSION: Our results provide evidence that concurrent immunopositivity with cyclin D1 and BCOR is helpful in distinguishing CCSK from its morphologic mimics.

ETV6-NTRK3 in congenital mesoblastic nephroma: A report of the SIOP/GPOH nephroblastoma study.

BACKGROUND: Congenital mesoblastic nephroma (MN) is a rare pediatric renal tumor representing approximately 5% of all pediatric renal tumors. Three different types of MN are distinguished histologically: classical, cellular, and mixed. A frequent genetic alteration is the translocation t(12;15) resulting in a fusion of the ETV6 gene on 12p13 and the NTRK3 gene on 15p15 that occurs almost exclusively in cellular MN. The aim of this study was to determine translocation status of a large cohort of MN with respect to tumor subtype and outcome. PROCEDURE: In total, clinical data from 111 patients were available. Sixty-seven tumors were classical MN (51%), 29 cellular MN (31%), and 15 were mixed MN (18%). From these 111 cases, 79 were analyzed by FISH and RT-PCR. RESULTS: All classical and mixed MN were translocation negative. Seventeen out of 29 (58%) cellular MN harbored the ETV6-NTRK3 translocation. Five-year relapse-free survival (RFS) and overall survival (OS) were 93.2% and 96.8% for the complete cohort. All seven relapses occurred in translocation negative tumors. Five-year RFS was significantly inferior for cellular and mixed MN compared to classic MN (89%, 80%, and 98%), whereas 5-year OS was similar (93%, 96%, and 98%). Within the group of cellular MN, patients having translocation-positive tumors had a significantly superior RFS (5-year RFS: 100% vs. 73%). CONCLUSION: The majority of cellular MNs harbor the ETV6-NTKR3 gene fusion, whereas all classic- and mixed-type MNs were translocation negative. Within the cellular subgroup, patients having translocation-positive tumors had a significantly superior RFS.

Diffuse and strong cyclin D1 immunoreactivity in clear cell sarcoma of the kidney.

AIMS: Distinguishing clear cell sarcoma of the kidney (CCSK) from other paediatric malignancies, particularly blastema-rich Wilms tumour (WT) and congenital mesoblastic nephroma (CMN), is challenging. Specific immunohistochemistry for CCSK does not exist, and diagnosis rests upon histopa thology. Recently, the YWHAE-FAM22 rearrange ment, identical to that in endometrial stromal sarcoma (ESS), has been identified in CCSKs. As this fusion results in overexpression of cyclin D1 in ESS, we postulated that overexpression would also occur in CCSK; cyclin D1 immunohistochemistry could then be used to differentiate CCSK from other tumours. The goal of this study was therefore to evaluate the utility of cyclin D1 immunohistochemistry in identifying CCSK and helping to differentiate it from its mimics. METHODS AND RESULTS: Cyclin D1 expression was evaluated in 59 renal tumours-CCSK (14), WT (25), rhabdoid tumour (four), Ewing sarcoma (five), and CMN (11)-and four neuroblastomas. All 14 CCSKs showed diffuse and strong reactivity. In contrast, the blastematous component of most WTs showed only rare positive nuclei, that of rhabdoid tumours showed rare to focal immunoreactivity, and that of more than half of CMNs showed weak or focal immunoreactivity. Most Ewing sarcomas and all neuroblastomas showed diffuse moderate to strong staining. CONCLUSIONS: Cyclin D1 is most helpful in distinguishing CCSK from WT, rhabdoid tumour, and some CMNs, but not from neuroblastoma or Ewing sarcomas.

Glypican 3 overexpression in primary and metastatic Wilms tumors.

Glypican 3 (GPC3), a heparan sulfate proteoglycan, plays a role in cell growth and differentiation. Mutations of the GPC3 gene are responsible for Simpson-Golabi-Behmel syndrome, which is characterized by anomalies of postnatal overgrowth and an increased risk of developing pediatric malignancies, mostly Wilms tumor and liver cancer. In order to understand the possible role of GPC3 in renal development and Wilms tumor formation, we analyzed messenger RNA (mRNA) and protein levels of GPC3 in sporadic Wilms tumors and compared it to normal kidneys and other common renal epithelial tumors. By using Affymetrix HGU133 oligonucleotide gene expression microarray data from 191 renal tumors and 12 normal kidneys, we found significant overexpression of GPC3 in Wilms tumors (p < 0.01), with 3.5-fold higher expression in comparison to normal kidneys and 6.5-fold higher than any type of renal tumors. The GPC3 gene product in Wilms tumor was further evaluated by immunohistochemistry and quantified by an automated image analysis. Cytoplasmic and membranous GPC3 immunoreactivity was present in 77 % of primary Wilms tumors (23/30), 93 % of metastatic Wilms tumors (13/14), 50 % of metanephric adenomas (4/8), 33 % of congenital mesoblastic nephromas (2/6), 100 % of nephrogenic rests (11/11), and 100 % of fetal kidneys (5/5). GPC3 staining was predominantly identified in blastemal and epithelial components of Wilms tumors, similar to that of fetal non-neoplastic kidney. All adult renal tumors (n = 60) and normal kidneys (n = 15) were GPC3 negative. These findings suggest the utility of GPC3 in differential diagnosis and follow-up of Wilms tumors. Our data also indicate that GPC3 is an oncofetal protein with a potential therapeutic value.

Evaluation of CITED1, SIX1, and CD56 protein expression for identification of blastemal elements in Wilms tumor.

OBJECTIVES: Successful further treatment of Wilms tumors (WTs) after preoperative chemotherapy and surgery depends on correct histopathologic risk stratification, including quantification of remaining blastemal elements. In the present study, we assessed the usefulness of protein markers for the detection of WT blastema. METHODS: Expression of the candidate blastemal protein markers CITED1, SIX1, and CD56 was evaluated by immunofluorescence regarding sensitivity and specificity for staining blastema in a tissue microarray containing cores from 30 WTs, a small number of rarer pediatric renal neoplasms, and normal postnatal kidney. RESULTS: CITED1, SIX1, and CD56 were expressed in blastema in 100%, 89%, and 74%, respectively, of the WTs with this component present. However, they were also expressed in 64%, 25%, and 79%, respectively, of epithelial WT elements and 48%, 52%, and 62%, respectively, of stromal WT elements. CONCLUSIONS: SIX1 showed the highest specificity, CITED1 the highest sensitivity, and CD56 low specificity and sensitivity for detection of postchemotherapy WT blastema. Cytokeratin staining proved to be a useful way to determine rudimentary tubular elements not readily recognized by routine staining.

Cellular metanephric stromal tumor in a postmenopausal woman: a case report with review of the literature.

Metanephric stromal tumor (MST) of the kidney is a rare pediatric neoplasm which has rarely been reported in adults. The authors present a case of MST, cellular type, an unreported variant, in a 56-year-old postmenopausal woman. The 9.0-cm tumor was solid, unencapsulated, and well circumscribed, with a firm homogeneous cut surface. The tumor was purely stromal with dense spindle-cell proliferations displaying prominent schwannoma-like architecture, intratumoral angiodysplasia, and entrapped native renal tubules with "onion-skin" tumor collarettes. The tumor stroma expressed CD34, estrogen, and progesterone and did not express desmin, smooth muscle actin, S-100, or TLE-1. Considering the characteristic morphology and immunophenotype, a diagnosis of "metanephric stromal tumor, cellular type," was made. This is an exceptionally rare disease manifestation in an adult patient and the first description of MST with such high stromal cellularity, making this case unique in both clinical and pathological presentation.

Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: a Children's Oncology Group study.

Infantile fibrosarcoma (IFS; also known as cellular congenital mesoblastic nephroma, CMN, when in the kidney) is a rare, undifferentiated tumour often characterized by the ETV6-NTRK3 fusion transcript. Our goal was to identify downstream pathways, diagnostic markers and potential therapeutic targets for IFS/CMN. Global gene expression, reverse-phase protein array and ETV6-NTRK3 fusion analyses were performed on 14 IFS/CMN and compared with 41 other paediatric renal tumours. These analyses confirm significant receptor tyrosine kinase (RTK) activation, with evidence of PI3-Akt, MAPK and SRC activation. In particular, GAB2 docking protein, STAT5-pTyr-694, STAT3-pSer-729 and YAP-pSer-127 were elevated, and TAZ-pSer-89 was decreased. This provides mRNA and proteomic evidence that GAB2, STAT activation and phosphorylation of the Hippo pathway transcription co-activators YAP and TAZ contribute to the RTK signal transduction in IFS/CMN. All IFS/CMN tumours displayed a distinctive gene expression pattern that may be diagnostically useful. Unexpectedly, abundant ETV6-NTRK3 transcript copies were present in only 7/14 IFS, with very low copy number in 3/14. An additional 4/14 were negative by RT-PCR and absence of ETV6-NTRK3 was confirmed by FISH for both ETV6 and NTRK3. Therefore, molecular mechanisms other than ETV6-NTRK3 fusion are responsible for the development of some IFS/CMNs and the absence of ETV6-NTRK3 fusion products should not exclude IFS/CMN as a diagnosis.

Parathyroid-hormone-related protein-mediated hypercalcemia in benign congenital mesoblastic nephroma.

Parathyroid hormone-related protein (PTHrP) mediated hypercalcemia of malignancy is rare in children, and even more so in the setting of a benign tumor. We report two infants with PTHrP-mediated hypercalcemia secondary to congenital mesoblastic nephroma and their outcome after removal of the benign tumor. Pre-operatively hypercalcemia was corrected with saline hydration, furosemide, calcitonin and/ or pamidronate. Following resection of the tumor serum PTHrP normalized. Immunohistochemical staining of tumor cells was positive for PTHrP. Post-operatively the infants developed elevated serum parathyroid hormone with low- normal serum Ca and P, and undetectable urinary Ca and P, probably due to their movement into bone. Children needed treatment with calcitriol, Ca and P supplementation for 6-12 weeks until PTH normalized and urinary Ca and P were detected, suggesting bone replenishment. We conclude that benign congenital mesoblastic nephroma can secrete PTHrP that can cause severe hypercalcemia; and following excision one should anticipate the development of a transient modified "hungry bone"-like condition requiring Ca, P and calcitriol therapy for several weeks accompanied by careful monitoring of mineral homeostasis.

PAX5 expression in nonhematopoietic tissues. Reappraisal of previous studies.

The Pax gene family encodes transcription factors with similar structures but distinctive roles in development and with limited expression in adult tissues. Reexpression of PAX proteins is frequently observed in human cancers, reflecting recapitulation of embryologic or developmental function. Defining expression of PAX family members is important in the immunohistochemical differential diagnosis of cancer, understanding oncogenesis, and defining targets for therapy. Immunostaining for PAX5 has become a commonly used technique in differential diagnosis of B-lineage hematologic malignancies. In seeking to define the range and degree of expression of PAX5 in nonhematologic pediatric cancers by immunohistochemical analysis with the anti-PAX5 monoclonal antibody routinely used in research and diagnosis, we observed strong immunostaining in a number of malignant tissues, including Wilms tumor. The pattern of expression of PAX5 in Wilms tumor was found to be identical to that of PAX2, raising the possibility of antibody cross-reactivity. This was subsequently confirmed by Western blotting and immunostaining of transfected cells and quantitative reverse transcriptase-polymerase chain reaction. Since the same PAX5 monoclonal antibody has been used consistently in the literature, these findings indicate a need for reappraisal of published PAX5 immunostaining results.

Multifaceted dysregulation of the epidermal growth factor receptor pathway in clear cell sarcoma of the kidney.

PURPOSE: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase overexpressed in a variety of human malignancies, against which targeted therapies have shown efficacy in lung and brain tumors. Clinical responses to EGFR inhibitors have been found to be highly dependent on the presence of activating mutations, whereas gene amplification, downstream activation of Akt, and abnormalities in PTEN are also reported predictive factors. We sought to evaluate these variables in pediatric renal tumors. EXPERIMENTAL DESIGN: We screened a series of 307 pediatric renal tumors for EGFR expression by immunohistochemistry and gene amplification by chromogenic in situ hybridization. In identifying a striking predilection for certain tumor types, we further analyzed the clear cell sarcomas of the kidney (CCSK) for mutations in EGFR and PTEN. RESULTS: Although only 23 of 177 (13.0%) nonanaplastic Wilms' tumors were EGFR positive, 4 of 11 (36.4%) anaplastic tumors showed receptor overexpression. In addition, 5 of 9 (55.6%) mesoblastic nephromas and 12 of 12 (100%) CCSKs were strongly immunoreactive for EGFR. In studying the CCSKs in more detail, we identified gene amplification in 1 of 12 (8.3%) cases and a somatic T790M EGFR mutation in a further case. These two samples additionally harbored mutations in PTEN. Downstream pathway activation, as assayed by phosphorylated Akt expression, was observed in 8 of 12 (66.7%) cases. CONCLUSIONS: Together, these data show dysregulation of the EGFR pathway at multiple levels in CCSKs. Identification of factors predictive of poor response to targeted therapy, including the drug resistance T790M mutation, may provide a rationale for upfront trials with irreversible inhibitors of EGFR in children with these tumors.

Duplication of the paternal IGF2 allele in trisomy 11 and elevated expression levels of IGF2 mRNA in congenital mesoblastic nephroma of the cellular or mixed type.

In a metaphase comparative genomic hybridization and fluorescence in situ hybridization study of 13 congenital mesoblastic nephroma (CMN) tumors, trisomy 11 was found in seven cellular or mixed type tumors, disomy 11 with other chromosome changes in two cellular type tumors, and no chromosome changes in four classical type tumors. Reverse-transcription (RT)-PCR analysis detected the ETV6-NTRK3 fusion transcript in all eight cellular or mixed type tumors examined, but not in four classical type tumors. All seven tumors with trisomy 11 showed duplication of the paternal IGF2 allele, and six cellular or classical type tumors with disomy 11 showed one paternal and one maternal allele of IGF2, analyzing the methylation status of the sixth CTCF site of the H19-differentially methylated region. Allelic expression study using the ApaI/AvaII polymorphism site at exon 9 of IGF2 showed retention of imprinting in all seven tumors examined. Quantitative real-time RT-PCR analysis showed higher expression levels of IGF2 mRNA in three of three cellular type tumors with trisomy 11, in one cellular type tumor with disomy 11, and in three of four classical tumors than in fetal kidneys or normal kidney tissues. Thus, duplicated paternal IGF2 resulted in elevated IGF2 mRNA levels, and may provide CMN or its precursor cells with a proliferative advantage. The mechanism explaining that some cellular or classical type tumors with disomy 11 also showed elevated IGF2 mRNA levels remains unresolved. IGF2 clearly plays an important role in the tumorigenic process of CMN, although it is difficult to assess its exact role.

Cystic nephroma and mixed epithelial and stromal tumor of kidney: a detailed clinicopathologic analysis of 34 cases and proposal for renal epithelial and stromal tumor (REST) as a unifying term.

Cystic nephroma (CN) and mixed epithelial and stromal tumor (MEST) are rare benign renal neoplasms that have overlapping clinical and morphologic features, including predominance in middle-aged women, variably cystic architecture, eosinophilic cells, and hobnail cells lining the cysts and ovarian-type stroma. The aim of this study was to analyze and compare the histologic features and immunohistochemical profile of these tumors. We studied 34 cases from 5 large academic institutions. Twenty tumors were diagnosed as CNs, 18 in women and 2 in men, their age ranged from 24 to 63 (mean 48; median 50) years. Fourteen tumors were diagnosed as MESTs, all in women, their age ranged from 26 to 84 (mean 52; median 51) years. Histologically, all tumors were well-circumscribed except for one MEST. The stromal/epithelial ratio was approximately 2.3 in MESTs versus 0.3 in CNs; cellular ovarian-type stroma composed 45% of the stroma in MESTs and 12% of the stroma of CNs. Stromal hyalinization was prominent in both. Five MESTs showed stromal luteinization. In the epithelial component, the relative amount of large cysts, medium to small cysts, and phyllodes-type glands was: 65%/25%/10% in CNs versus 25%/40%/35% in MESTs. The epithelial component ranged from flat to cuboidal to hobnail cells in both types of tumors. No significant atypia of either component was seen, although the epithelial cells showed reactive changes. Immunohistochemical stains for estrogen receptors and progesterone receptors showed 62% and 85% positivity in the stromal component of MESTs versus 19% and 40% in CNs. CD10 positivity was seen in 77% of MESTs versus 50% of CNs, calretinin was seen in 69% of MESTs versus 41% of CNs, and inhibin in 42% of MESTs versus 36% of CNs, although the staining was focal. Follow-up in both categories of tumors (mean 3.2 y, median 3 y for CNs and mean 2.5 y, median of 2 y for MESTs) showed no evidence of recurrence or metastases in keeping with their benign nature. This study highlights the remarkable similarity between CN and MEST in sex predilection, age distribution, and morphologic attributes of both the epithelial and stromal components and immunohistochemical profile albeit with variation in individual categories with higher prevalence of stromal to epithelial ratio, prominent ovarian stroma, smaller cysts with phyllodes glands pattern and stromal luteinization being more common in MEST; and large cysts, thin septae and low stromal to epithelial ratio in CN. The presence of ovarian-type stroma and müllerian related immunohistochemical markers raises the possibility that these tumors may originate from müllerian remnants misplaced during embryogenesis. On the basis of detailed morphologic analysis of this series of CN and MEST, we propose a unifying term of "renal epithelial and stromal tumor" (REST) to encompass the spectrum of findings observed in these tumors at least until new molecular studies can prove or disprove this challenging hypothesis.

Mixed epithelial and stromal tumor of the kidney and cystic nephroma share overlapping features: reappraisal of 15 lesions.

CONTEXT: Cystic nephroma is a rare cystic tumor, which only recently has been recognized as an exclusively adult lesion. Mixed epithelial and stromal tumor of the kidney is also a rare, recently recognized, biphasic tumor composed of tubular and cystic elements embedded in grossly recognizable spindle cell stroma. The histogenesis of both lesions is unclear. OBJECTIVES: To compare clinical phenotype, morphology, and immunohistochemistry in mixed epithelial and stromal tumor of the kidney and cystic nephroma in order to explore the relationship between these 2 lesions. DESIGN: Fifteen biphasic lesions (8 mixed epithelial and stromal tumors of the kidney and 7 cystic nephromas) were studied. All cases were reviewed and subjected to detailed pathologic studies, and the results were correlated with clinical findings. RESULTS: Mixed epithelial and stromal tumor of the kidney occurred exclusively in women aged 36 to 80 years (mean, 49.7 years), all of whom had a history of estrogen therapy and/or obesity. Cystic nephroma occurred in both sexes; patients were aged 22 to 71 years (mean, 50.4 years), and a history of hormonal therapy was present on occasion. All 15 lesions were benign. Lesions varied by size, the proportion of cystic component, and the amount and cellularity of stroma. However, in all lesions tested, the stroma was diffusely positive for smooth muscle actin, and smooth muscle differentiation was confirmed by electron microscopy. In mixed epithelial and stromal tumors of the kidney, the stroma was positive for estrogen and progesterone receptors in 4 of 5 lesions tested. In cystic nephroma, focal positivity for hormone receptors was seen in 2 of 7 tumors tested; both positive lesions were from women. The epithelial lining in both mixed epithelial and stromal tumor of the kidney and cystic nephroma lesions was variable with regard to shape, cytoplasmic appearance, and immunophenotype (with focal positivity for CD10, cytokeratin 7, high-molecular-weight keratin, and Ulex europaeus detectable in both lesions). This pattern suggests variable differentiation, which was confirmed by electron microscopic studies (performed in 1 case). CONCLUSIONS: While mixed epithelial and stromal tumor of the kidney has a strong association with the female sex and hormonal milieu, cystic nephroma can affect both sexes and, on occasion, may also have hormonal associations. Morphologically, there is considerable overlap between both lesions, which suggests that they may represent opposite ends of the spectrum of the same process. Our studies also suggest that the tubules may be entrapped rather than comprising an intrinsic component of the tumor. However, further studies, including molecular studies, are needed to support this hypothesis.

KIT expression in normal and neoplastic renal tissues: immunohistochemical and molecular genetic analysis.

Renal chromophobe cell carcinomas (ChCC) and oncocytomas express KIT. This character seems to reflect their common histogenesis from distal nephrons. In the normal kidney, however, the expression and localization of KIT are unclear. KIT expression in angiomyolipoma and congenital mesoblastic nephroma (CMN), is still controversial. c-kit mutations are reportedly rare in ChCC, but there is little information in other renal neoplasms, and no reported data on mutations of platelet-derived growth factor receptor (PDGFR). In order to address these issues the authors examined five ChCC, five oncocytomas, seven papillary cell carcinomas, two collecting duct carcinomas, 12 angiomyolipomas, and three CMN, as well as 10 normal renal tissues. In the normal kidney KIT was specifically expressed in the distal nephrons. Nine of 12 (75%) angiomyolipomas contained scattered KIT-positive cells, whereas all three CMN were completely negative for KIT. The presence of KIT-positive cells in angiomyolipomas was likely to correspond to that of melanocytic marker-positive cells, which mainly showed epithelioid morphology. Polymerase chain reaction-single-strand conformation polymorphism showed no evidence of mutations of c-kit or PDGFR in any of the tumors examined.

Gene expression profiling of mesoblastic nephroma and Wilms tumors--comparison and clinical implications.

OBJECTIVES: To better understand the molecular mechanisms in the tumorigenesis and progression of mesoblastic nephroma (MN), we studied its gene expression profiles. MN is the most common tumor of the neonatal kidney. It occurs in a younger age group than the Wilms tumor (WT). To date, very little is known about the etiology and pathogenesis of MN. METHODS: Using microarrays containing 22,943 cDNA, we analyzed the expression profiles of MN and compared its expression profiles with those of several other types of kidney tumors, including WT. RESULTS: MN has a distinct molecular signature that clusters close to the WT, suggesting that both types of tumor share some similarity in gene expression and biology. When comparing the two profiles closely, we identified a number of genes that are commonly upregulated in both tumors, including insulin-like growth factor 2, thrombospondin 4, and mesenchyme homeo box 1. We also identified a set of genes that distinguish MN from WT, some of which may underlie the difference in their behaviors and can be used as diagnostic markers. Among this group of genes, topoisomerase II-alpha, highly expressed in WTs, is not overexpressed in MN. Immunohistochemical staining of topoisomerase II-alpha in additional cases of WTs and MNs confirmed this distinction further. CONCLUSIONS: The results of our study demonstrated that MN has a distinct gene expression profile and that some of the newly identified genes can be potentially used as novel diagnostic markers.

KIT expression in fetal, normal adult, and neoplastic renal tissues.

BACKGROUND: KIT is a transmembrane tyrosine kinase receptor, expressed in high amounts in various normal cells. In addition, c-kit mutation or activation is a major pathogenetic event in certain tumours (such as gastrointestinal stromal tumours). There are only limited data in the literature on the expression of KIT in normal and neoplastic renal tissues. AIMS: To investigate KIT expression in normal and neoplastic renal tissues. METHODS: KIT expression was evaluated by means of immunohistochemistry in paraffin wax embedded sections from 67 tissue samples. RESULTS: Eight of eight fetal kidneys, and 10 of 10 normal adult kidneys revealed cytoplasmic staining of renal tubules. The three cases of renal dysplasia studied expressed KIT in their normal and aberrant tubules. Two of 13 conventional renal cell carcinomas (RCCs), two of seven papillary type RCCs, four of seven chromophobe type RCCs, none of six nephroblastomas, seven of seven oncocytomas, two of two mesoblastic nephromas, and two of four angiomyolipomas were positive. CONCLUSION: KIT is expressed in normal fetal and adult renal tubules, and in a subset of renal tumours. The expression of KIT in these renal tumours may prove to have diagnostic relevance and/or therapeutic implications.

Expression of WT-1, Bcl-2, and CD34 by primary renal spindle cell tumors in children.

The confident diagnosis of renal spindle cell tumors in children is often difficult. An immunohistochemical study of WT-1, Bcl-2, and CD34 was performed to determine their expression profiles and to assess the potential utility of these immunohistochemical markers in the differential diagnosis of 36 cases of renal spindle cell tumors of childhood. The cases included 11 stromal predominant Wilms tumors, 12 cellular mesoblastic nephromas, 9 clear cell sarcomas of the kidney (CCSK), and 4 monophasic synovial sarcomas. WT-1 was uniformly positive in primitive undifferentiated stromal Wilms tumors (6 of 6) and negative in the differentiating and differentiated stromal elements of Wilms tumors (0 of 5). WT-1 was also negative in cellular mesoblastic nephromas (0 of 12), CCSKs (0 of 12), and synovial sarcomas (0 of 4). Bcl-2 was expressed in all stromal Wilms tumors (11 of 11), all synovial sarcomas (4 of 4), some CCSKs (4 of 9), and none of the cellular mesoblastic nephromas (0 of 12). Although CD34 was absent in the tumor cells of all the tumors studied (0 of 36), CD34 immunohistochemistry nicely demonstrated the evenly distributed septal capillaries characteristic of CCSK in all 9 cases of this tumor. We conclude that a combination of WT-1 and Bcl-2 immunohistochemistry may aid in the distinction of stromal Wilms tumor, monophasic synovial sarcoma, cellular mesoblastic nephroma, and CCSK.