REVIEW ARTICLE

Wilms Tumor: An Update Turki Al-Hussain, MD,* Afshan Ali, MD,w and Mohammed Akhtar, MD, FCAP, FRCPA, FRCPath*

Abstract: Wilms tumor (WT) is the most common neoplasm of the kidney in children. It is an embryologic tumor that histologically mimics renal embryogenesis and is composed of a variable mixture of stromal, blastemal, and epithelial elements. Nephrogenic rests, generally considered to be precursor lesions of the WT, are foci of the embryonic metanephric tissue that persist after the completion of renal embryogenesis. These are classified as perilobar and intralobar based on their location and maybe present as single or multiple foci. Intralobar and perilobar rests and the tumors arising from these rests differ morphologically and are characterized by 2 different sets of genetic abnormalities involving 2 adjacent foci, WT1 and WT2, on the short arm of chromosome 11. WTs arising in the intralobar rests tend to be stromal predominant and have a mutation or deletion of WT1. Germline mutation in WT1 may be associated with syndromic conditions such as WAGR and DenysDrash syndromes. Perilobar rests and their corresponding tumors usually have loss of imprinting/loss of heterozygosity involving WT2, which contains several parentally imprinted genes. Loss of function of these genes, if present constitutionally, may be associated with Beckwith-Wiedemann syndrome or may result in isolated hypertrophy. Abnormalities in several other genes may also be seen in WT. These include WTX, (on chromosome X), CTNNB1 (chromosome 3), and TP53 (chromosome 17) among others. WT with loss of heterozygosity at 1p and 16q may have poor prognosis, requiring aggressive therapy. Treatment modalities for WT have evolved over many decades, primarily through the efforts of Dr J Bruce Beckwith at National WT study. This work is now being carried out by Children Oncology Group in North America and International Society of Pediatric Oncology in Europe. Although their therapeutic approaches are somewhat different, both have reported excellent results with equally high cure rates. Key Words: Wilms tumor, kidney, nephrogenic, nephroblastoma, syndromes, mutations

(Adv Anat Pathol 2014;21:166–173)

W

ilms tumor (WT), also called nephroblastoma, is an embryonal malignant neoplasm of the kidney usually diagnosed in young children. In North America, WT affects approximately 1 of every 8000 to 10,000 children. The age at presentation for male patients is lower (36.5 mo) than for female patients (42.5 mo). WT is the most common renal tumor in children, although it may be rarely seen in adults or in extrarenal locations. The usual clinical presentation of

WT is that of an abdominal mass in a child who appears to be otherwise healthy. Multicentric or bilateral WT may be seen in 5% to 10% of children. Average age of presentation for patients with bilateral WT is 30 to 33 months. WT has the potential for both local spread and distant metastasis. In an overwhelming majority of cases, WT is sporadic, but in 5% to 10% of patients it may be associated with a range of genetic syndromes or congenital anomalies.1–4

PATHOLOGIC FEATURES Histologically, the usual appearance of WT is that of a mixed pattern with variable proportions of 3 cellular components, namely, blastemal, epithelial, and stromal. Each one of these cellular elements may show different degrees of differentiation. In many cases, only 1 or 2 of these cellular components may be represented. The blastemal component is the least differentiated cellular element and consists of densely packed small-sized to medium-sized cells with small round nuclei and scanty cytoplasm. The cells may be arranged diffusely or may show an organoid arrangement including serpentine, nodular, and basaloid patterns (Fig. 1). The stromal component is composed of undifferentiated mesenchymal cells but may also show variably differentiated smooth and skeletal muscle cells, adipose tissue, cartilage, and bone (Fig. 2). The epithelial component simulates the embryologic development of the kidney and may manifest several morphologic patterns such as primitive epithelial structures mimicking rosettes, variably differentiated tubules, and glomerular structures (Fig. 3). Depending on the proportions of the individual cellular components, WTs may be divided into subtypes, namely, epithelial, blastemal, and stromal. WT with more than two-third epithelial components is designated as epithelial, whereas a tumor with more than two-third stromal elements may be categorized as stromal. If none of the components is predominant, the tumor is designated as mixed3–9 (Fig. 4). Tumors with >50% component of the heterologous, stromal, or epithelial elements have been called by some as teratoid WT. Another variant composed predominantly of mature rhabdomyomatous component has been called fetal rhabdomyomatous nephroblastoma (Fig. 5). Both subtypes may have favorable clinical outcome if the tumor is completely resected; however, they generally do not respond to chemotherapy.10,11

ANAPLASIA From the Departments of *Pathology and Laboratory Medicine; and wPediatric Hematology/Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Kingdom of Saudi Arabia. The authors have no NIH funding or conflicts of interest to disclose. Reprints: Mohammed Akhtar, MD, FCAP, FRCPA, FRCPath, Department of Pathology and Laboratory Medicine (MBC 10), King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia (e-mail: makhtar69@ kfshrc.edu.sa). All figures can be viewed online in color at http://www.anatomic pathology.com Copyright r 2014 by Lippincott Williams & Wilkins

166 | www.anatomicpathology.com

Several large studies have demonstrated that the presence of anaplasia in WT is associated with lack of response to chemotherapy with an adverse outcome.9,12 Anaplasia is defined as the presence of marked nuclear enlargement, pleomorphism, and hyperchromasia along with large atypical multipolar mitoses (Fig. 6). WTs without anaplasia are designated as tumors of “favorable histology.” Anaplasia may be present in approximately 5% of the WTs and may be characterized as focal or diffuse. Focal anaplasia is present in 1 or only a few sharply defined areas Adv Anat Pathol



Volume 21, Number 3, May 2014

Adv Anat Pathol



Volume 21, Number 3, May 2014

Wilms Tumor

FIGURE 1. A, Blastema predominant Wilms tumor with a solid growth pattern. B, Nodular pattern of blastema. C, Basaloid pattern of blastema.

without evidence of marked nuclear atypia in the rest of the tumor. In contrast, diffuse anaplasia is not clearly demarcated from the nonanaplastic part of the tumor, may be present within intrarenal vascular extension of the tumor, or in the tumor at an extrarenal location or in a metastatic site. Any focus of anaplasia detected in a random needle core biopsy is considered as diffuse. Anaplasia is usually seen in the blastemal or epithelial elements of WT. The stromal elements may also be involved, although anaplasia limited to the stromal cells is very rare.2,3,13,14

PRECURSOR LESIONS OF WILMS TUMOR (NEPHROGENIC RESTS) WT is generally considered to arise from precursor lesions, which are cellular rests persisting after the embryologic development of the kidney is complete. The embryologic development of the kidney starts with the mesonephric duct opening into the cloaca (fourth week of gestation) and, subsequently, giving rise to a diverticulum called ureteric bud. The ureteric bud grows cranially into the intermediate mesoderm where it is surrounded by a cap of condensed mesodermal cells. This cap of cells is the metanephric blastema.15 The ureteric bud divides many times and it eventually gives rise to the pelvicalyceal system of the kidney, and the collecting tubules and ducts. The metanephric blastema aggregates around the branches of the ureteric bud and differentiates into the nephrons as well as supporting connective elements of the kidney. Renal organogenesis is usually complete by 36 weeks of gestation by which time all the metanephric blastema has fully

FIGURE 2. Wilms tumor with a stromal predominant pattern. r

2014 Lippincott Williams & Wilkins

differentiated into renal parenchyma. In some cases, however, part of the metanephric mesoderm may not undergo full differentiation and maturation and may persist after birth as nephrogenic rests. These rests may be found in up to 1% of normal kidneys, in 30% to 40% of kidneys with sporadic WT, and in almost 100% of cases with bilateral WT. The presence of these rests may also have an association with a variety of syndromic conditions and congenital anomalies.2,3,16–19 There are 2 major types of nephrogenic rests, namely, perilobar (PLNR) and intralobar (ILNR), which have different localizations within the kidney3,18–23 (Figs. 7–9). The median age of patients presenting with PLNRs and Wilms tumor is 35.5 months, whereas that with ILNRs and the tumor is 18.5 months. Intralobar rests are less common, representing approximately 10% of all the nephrogenic rests. These are usually solitary, and tend to be situated centrally within the renal lobe with poorly defined, irregular, and intermixed margins (Figs. 7, 9). Occasionally, these rests may be located in the extrarenal tissues such as the renal sinus or in the wall of the calyxes.19 Histologically, these rests are composed of stroma, blastema, and tubules, although stromal elements tend to be dominant. Perilobar rests are much more common (90%), are located at the periphery of the renal lobe, usually under the renal capsule, and are often multiple. These are usually sharply demarcated but not encapsulated, and are most often composed of blastemal elements and tubules with little stromal component (Figs. 8, 9). Both types of nephrogenic rests may be

FIGURE 3. Epithelial predominant Wilms tumor with prominent tubular differentiation.

www.anatomicpathology.com |

167

Al-Hussain et al

Adv Anat Pathol



Volume 21, Number 3, May 2014

FIGURE 4. Mixed pattern of Wilms tumor with variable proportions of epithelial, blastemal, and stromal components.

FIGURE 6. Anaplastic Wilms tumor with tumor cells containing enlarged hyperchromatic nuclei and multipolar mitoses.

described as dormant, sclerosing, hyperplastic, and adenomatous depending on their size, cellularity, and degree of cellular proliferation. Their natural history is probably that of gradual regression as these are not seen in the adult kidney. The risk of malignant transformation is much higher in the ILNRs as compared with the PLNRs. Perilobar rests show a strong association with synchronous bilateral WT, whereas ILNRs tend to be associated with metachronous tumors.2,3,18–23 Anaplasia may rarely occur in nephrogenic rests, although the clinical significance of this finding is not clear.24 The term nephroblastomatosis is used to describe the presence of multiple nephrogenic rests and denotes a more extensive disease, which may be present as multiple nodules of the nephrogenic rest tissue. Diffuse hyperplastic nephroblastomatosis manifests as a diffuse overgrowth of embryonic rests, producing a thick rind that surrounds and enlarges one or both the kidneys (Fig. 9). Histologically, these lesions consist predominantly of blastemal elements with variable proportions of epithelial components that may be difficult to distinguish from WT, especially on a biopsy. Universal (panlobar) nephroblastomatosis is

extremely rare and denotes a complete replacement of the renal lobe by the nephrogenic tissue21–23 (Fig. 9). The preneoplastic nature of nephrogenic rests is supported by the fact that some of the genetic abnormalities that characterize the various types of WT are also present in the nephrogenic rests.25 Intralobar rests are characterized by mutations or deletions in WT1 (11p13) gene. Germline abnormality of WT1 may be associated with WAGR syndrome (WT-aniridia-genital anomalies-retardation) or Denys-Drash syndrome (DDS), a condition that affects the development of the kidneys and genitalia and most often affects males. Fraser syndrome is another condition caused by germline mutations in WT1 and is probably a variant of DDS.26 WTs arising from ILNR typically show stromal predominant histology and may manifest heterologous differentiation (smooth and skeletal muscle elements, bone, and cartilage). On the contrary, perilobar rests show allelic loss at WT2 (11p15), which may also be detectable in the adjacent normal kidney. The tumors arising from these nests usually have predominance of epithelial or blastemal elements with limited stromal differentiation (Fig. 9). Some of the patients with PLNR may have germline abnormality

FIGURE 5. Embryonal rhabdomyomatous nephroblastoma virtually entirely composed of striated muscle elements.

FIGURE 7. Intralobar nephrogenic rest with a stromal predominant pattern.

168 | www.anatomicpathology.com

r

2014 Lippincott Williams & Wilkins

Adv Anat Pathol



Volume 21, Number 3, May 2014

Wilms Tumor

Somatic changes of WT1 are present in approximately 20% of sporadic WTs and are limited to the tumor and adjacent nephrogenic rests. WT1 is constitutionally mutated in patients with DDS but is usually deleted in patients with WAGR syndrome. Germline abnormalities may also be found in children with genetic predisposition to WT without any syndromic condition.2,3,18,19

WILMS TUMOR 2 LOCUS

FIGURE 8. Perilobar nephrogenic rest composed mostly of the embryonic tissue with tubular differentiation.

in WT2 clinically manifesting as Beckwith-Wiedemann syndrome (BWS) or isolated hemihypertrophy.2,3,18,19

GENETICS OF WILMS TUMOR WT, like many other types of cancers, develops as a result of abnormalities of genes that are normally responsible for cellular growth, differentiation, and proliferation. Most WTs occur in children who are otherwise in good health. Approximately, 5% of such children have underlying constitutional mutations at 11p13 (WT1) or epigenetic defects at chromosome 11p15 (WT2) that predispose to WT. These patients are phenotypically normal without any syndromic conditions or genitourinary abnormalities. WTs, in patients with germline WT1 mutations, are more likely to be bilateral or multicentric and present at an earlier age. Another 10% to 15% also has constitutional genetic defects in WT1 or WT2, but have manifestations of one of the known syndromic conditions such as WAGR, DDS, and BWS among others (Fig. 10). An overwhelming majority of WTs, however, are sporadic and only have somatic mutations, which are limited to the neoplastic tissue, and accompanying nephrogenic rests. In addition to the abnormalities of WT1 and WT2, several other genes including CTNNB1, WTX, and TP53 have also been implicated in various stages of tumorigenesis of WT.2,3,18,19 During the embryologic development of the kidney and gonads, WT1 is required for normal organogenesis. In the kidney, it plays a crucial role in the development and maintenance of the ureteric bud and is responsible for the mesenchymal-epithelial transition in the metanephric mesoderm, leading to the differentiation of renal blastema into nephrons.27–29 The WT1 gene is located on the short arm of chromosome 11 (11p13). It spans approximately 50 kb and includes 10 exons, encoding a 3 kb mRNA. The carboxyl-terminal portion contains 4 zinc finger motifs, which form the DNA-binding domain (Fig. 11). WT1 can bind, through its zinc fingers, to the promoter regions of a multitude of putative downstream target genes. All mutations in WT1 alter the structure of the DNAbinding domain, which changes its ability to bind to DNA, resulting in loss of function.29–31 r

2014 Lippincott Williams & Wilkins

A second WT locus, WT2 gene, is also located on the short arm of chromosome 11 and maps to the region of 11p15.5, which contains a cluster of imprinted genes, of which insulin-like growth factor II (IGF2) and H19 have been studied most extensively. Insulin growth factor II gene encodes an embryonic growth factor, whereas H19 expresses a noncoding RNA, which functions as a tumor suppressor. Under normal conditions, IGF2 is imprinted such that it is paternally expressed while only maternally inherited allele of H19 is expressed. Loss of imprinting (LOI) of IGF2 may result in aberrant activation of IGF2 on the normally repressed maternal allele. In some cases, LOI may be associated with loss of the maternal allele with replacement by duplicated paternal allele (uniparental paternal duplication). The LOI and uniparental paternal duplication of IGF2 in WT are thought to be heavily influenced by the inactivation of H19 maternal allele because of hypermethylation. These changes result in the overexpression of IGF2 and reduced expression of H19. The changes in IGF2 and H19 seem to precede the formation of PLNR, as WT2 abnormalities are frequently present in these rests and occasionally even in adjacent apparently normal renal tissue.2,3,18,19,31–33 Abnormalities of WT2 are by far the most common genetic defect in sporadic WT. In a study on 35 sporadic primary WTs, >80% had somatic loss of heterzygosity (LOH) and LOI at 11p15.5. LOI or gene methylation is rarely found at other loci, supporting the specific role of LOI at IGF2 in WT.33 In most of the cases of WT, the underlying molecular aberrations may determine the type of histologic features of WT and the type of accompanying nephrogenic rests (ILNR vs. PLNR).34 Although this is true in most of the cases, exceptions do occur. Interestingly, WT in Asian children are less frequently associated with either nephrogenic rests or IGF2 loss, both of which are commonly seen in white children.35,36 In addition to WT1 and WT2 genes, a range of additional genes have been implicated in the pathogenesis and biology of WT. These genes may not be involved in the early stages of tumorigenesis, but seem to play a role in the progression of WT and may determine clinical behavior and prognosis.

WTX WTX gene is located on the X chromosome and is known to play a role in normal kidney development. Somatic mutations in WTX may be observed in 6% to 30% of sporadic WTs. Germline mutations in this gene cause a rare syndrome characterized by sclerosing skeletal dysplasia, osteopathia striata congenita with cranial sclerosis. Patients with this disease are generally not prone to develop WT.37 Nephrogenic rests are negative for WTX mutations, although rare exceptions do occur. Downregulation of WTX leads to increased signaling within the WNT signaling pathway.37–40 www.anatomicpathology.com |

169

Al-Hussain et al

Adv Anat Pathol



Volume 21, Number 3, May 2014

FIGURE 9. Diagrams depicting the various patterns of distribution of nephrogenic rests within the kidney. A, Perilobar rest. B, Intralobar rest. C, Panlobar rest. D, Diffuse hyperplasic perilobar rest.

TP53 Tumor-suppressor gene p53 is located on chromosome 17p13.1 and encodes the gene protein P53. It is the most frequently mutated gene in human malignant neoplasms. In normal cells, P53 protein is expressed at very low levels, but

170 | www.anatomicpathology.com

it plays a crucial role in many cellular processes including cellular proliferation and differentiation, apoptosis, and DNA repair.41 In WT, p53 expression may be associated with histologic evidence of anaplasia. Mutations of p53 are detected in up to 75% of WTs with anaplasia, indicating the r

2014 Lippincott Williams & Wilkins

Adv Anat Pathol



Volume 21, Number 3, May 2014

Wilms Tumor

tumor progression. They also found a strong association between mutations in WT2 and WTX and between abnormalities of WT1 and CTNNB1.32 Interestingly, this study also revealed a subset of WTs, which lacked mutations in any of the above-mentioned genes.

16q and 1p

FIGURE 10. Nephrogenic rests with genetic abnormalities along with corresponding syndromic conditions and the types of WTs. WT indicates Wilms tumor.

significance of this mutation as a prognostic marker in tumors with unfavorable histology. It is also thought that a favorable histology tumor may progress to an anaplastic tumor by acquiring a disruption of TP53 function. P53 mutations may also play a crucial role in tumor progression, relapse, and metastases. Although it does not seem to have a significant role in the genesis of WT, it may be an important marker of unfavorable prognosis.42,43

CTNNB1 CTNNB1 encodes b-catenin, a dual-function protein, regulating the coordination of cell-cell adhesion and gene transcription. Mutations and overexpression of b-catenin are associated with the activation of the classic canonical Wnt pathway and has been implicated in a range of cancers, including cancers of the liver, colorectum, breast, ovary, and endometrium. The overexpression of the Wnt pathway has been observed in a subset of WTs, mostly in tumors that also have chromosomal aberrations of WT1. CTNNB1 mutations and b-catenin overexpression are limited to the tumor cells and are not seen in the normal kidney or within the nephrogenic rests, indicating that CTNNB1 mutations may be acquired at a later stage of tumor development.44–47 Scott and colleagues conducted an extensive study on 125 WTs for abnormalities in all 5 genes (WT1, WT2, WTX, CTNNB1, and TP53). Of the 100 sporadic tumors, 69% revealed WT2 abnormalities and 12% had mutations in WT1. These mutations were considered fundamental to the initiation of WT, as these changes were also identifiable in accompanying nephrogenic rests. Other mutations (WTX 32%, CTNNB1 15%, and TP53 5%) were considered secondary in nature, unrelated to tumor initiation, but probably contributing to

FIGURE 11. Diagram depicting the WT1 gene and WT1 protein (see text for more details). WT indicates Wilms tumor. r

2014 Lippincott Williams & Wilkins

Studies have revealed LOH at 1p36 and 16q21-24 in 17% and 11% of WTs, respectively, suggesting the presence of tumor-suppressor or tumor-progressive genes at these locations. Patients with WTs characterized by the loss of these loci within the tumor had significantly worse relapsefree and overall survival rates.48 The mechanisms by which LOH 1p or 16q might be directly affecting the tumor response to therapy is not clear. It has been speculated that LOH at these loci may just be markers of changes elsewhere in the genome.49

MYCN Amplification of the MYCN oncogene has also been described in WT.50 It is usually associated with the diffuse anaplastic subtype of WT, although it may also be seen occasionally in WT without anaplasia. The increase in copy numbers of MYCN in WTs is usually modest as compared with that in neuroblastoma.

MANAGEMENT OF WILMS TUMOR: THE 2 APPROACHES The development of treatment protocols for WT represents an impressive success story attributable to a multinational collaborative effort. This has been made possible primarily because of the pioneering work by Dr J. Bruce Beckwith, who headed the National Wilms tumor study group in the United States. The outlook for patients with WT has changed markedly from the time when this tumor was considered universally fatal to the present era when >85% of the patients with localized disease can be completely cured, whereas those with metastatic disease have >70% chance of survival. Major research and randomized controlled trials conducted by several cooperative groups have played a crucial role in improving the prognosis of patients with WT. The 2 major groups that have contributed a great deal in refining approaches toward effective management of WT are the Children Oncology Group (COG) (previously National Wilms Tumor Study Group) in North America and the International Society of Pediatric Oncology (SIOP) in Europe. The Children’s Cancer Study Group in the United Kingdom has also coordinated efforts in this process.51 These groups have advocated 2 different approaches for the management of this tumor. In the COG protocol, surgical resection of WT is performed followed by histologic evaluation and accurate staging. This provides valuable information for identifying patients who require adjuvant chemotherapy. In the SIOP treatment protocol, patients are treated with chemotherapy (without a biopsy) to shrink the size of the tumor. This facilitates surgical resection and prevents tumor spillage during surgery. High-risk tumors are identified for more aggressive chemotherapy. Interestingly, the overall survival rate among WT patients managed by both approaches is approximately 90%.51–53 The SIOP protocol recognizes a new “blastemal subtype” of WT requiring intensive postsurgery chemotherapy. This subtype is diagnosed based on histologic response to www.anatomicpathology.com |

171

Al-Hussain et al

Adv Anat Pathol

prenephrectomy chemotherapy. In this subtype, the proportion of undifferentiated blastemal cells surviving after chemotherapy constitute >10 of the tumors in the resected specimen.3 This entity is not recognized in the COG protocol. COG, however, has recently added LOH on chromosomes 1p and 16q as markers for poor prognosis. Combined loss of 1p and 16q are used to identify a subset of patients in the favorable histology WT group for more aggressive therapy.3

ADULT WILMS TUMOR WT in adults is rare and the estimated incidence is only 0.2 cases per million. There are approximately 300 cases of adult WT reported in the literature.54–59 Kilton et al59 suggested diagnostic criteria for adult WT that include primary renal tumor in the age group of above 15 years, with histologic features of embryonic glomerulotubular structures with immature spindle or round cell stroma and no areas of tumor diagnostic of renal cell carcinoma. The genomic alterations involved in adult WT maybe different than WT in children, with the majority of chromosomes displaying uniparental disomies and microdeletions in genes involved in organogenesis.57 Adult WT has more aggressive clinical course and a higher tumor stage at the time of presentation, as well as worse outcome than pediatric WT probably because of the difficulty in diagnosis, inadequate staging, and undertreatment.56–60 Adult WT is a difficult tumor to study, because some of the previously considered adult WT may in fact be other more aggressive entities such as primary renal Ewing sarcoma and primary renal synovial sarcoma.61,62

EXTRARENAL WILMS TUMOR (ERWT) ERWT is a rare form of WT that occurs outside the kidney. It accounts for 3% of WTs with approximately 100 well-documented cases.63,64 It has been reported in a variety of locations including the retroperitoneum, inguinal and paratesticular region, female genital tract, bladder, thorax, and lambosacral region.63–65 On the basis of the National Wilms tumor study, the diagnosis of an ERWT should fulfill 3 criteria. First, a primary tumor in the kidney should be excluded. Second, the triphasic histology pattern (blastemal, epithelial, and stromal) should be present. Third, there should be no evidence of teratoma or renal cell carcinoma on thorough examination of the entire tumor.66 No staging system for ERWT has been worked out, although the staging similar to that used for intrarenal WT may be applicable. The prognosis of ERWT also seems to be similar to that of intrarenal WT. The origin of ERWT is unclear; possibilities include origin from heterotopic metanephric blastema, persistent mesonephric duct remnants, and intermediate mesoderm.65–68 REFERENCES 1. Breslow N, Olshan A, Beckwith JB, et al. Epidemiology of Wilms Tumor. Med Pediatr Oncol. 1993;21:172–181. 2. Dome JS, Huff V. Wilms tumor overview. In: Pagon RA, Adam MP, Bird TD, et al, eds. GeneReviewst [Internet]. Seattle, WA: University of Washington; 2003. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1294/. 3. Vujanic GM. Renal tumours of childhood: an overview. Diagn Histopathol. 2009;15:501–509. 4. Beckwith JB, Palmer NF. Histopathology and prognosis of Wilms tumor. Results from the First National Wilms’ Tumor Study. Cancer Met Rev. 1978;41:1937–1948.

172 | www.anatomicpathology.com



Volume 21, Number 3, May 2014

5. Weirich A, Leuschner I, Harms D, et al. Clinical impact of histologic subtypes in localized non-anaplastic nephroblastoma treated according to the trial and study SIOP-9/GPOH. Ann Oncol. 2001;12:311–319. 6. Murphy WM, Grignon DJ, Perlman EJ. Kidney tumors in children. In: Murphy WM, Grignon DJ, Perlman EJ, eds. Tumors of the kidney, bladder, and urinary structures. Atlas of tumor pathology, 4th Series, Fascicle 1. Washington, DC: Armed Forces Institute of Pathology; 2004:57–64. 7. Eble JN, Sauter G, Epstein JI, et al. Tumours of the Urinary System and Male Genital Organs. Lyon: IARC; 2004. 8. Verschuur AC, Vujanic GM, Van Tinteren H, et al. Stromal and epithelial predominant Wilms tumours have an excellent outcome: the SIOP 93 01 experience. Pediatr Blood Cancer. 2010;55:233–238. 9. Beckwith JB, Zuppan CE, Browning NG, et al. Histological analysis of aggressiveness and responsiveness in Wilms’ tumor. Med Pediatr Oncol. 1996;27:422–428. 10. Sultan I, Ajlouni F, Al-Jumaily U, et al. Distinct features of teratoid Wilms tumor. J Pediatr Surg. 2010;45:e13–e19. 11. Pollono D, Drut R, Tomarchio S, et al. Fetal rhabdomyomatous nephroblastoma: report of 14 cases confirming chemotherapy resistance. J Pediatr Hematol Oncol. 2003;25:640–643. 12. Dome JS, Cotton CA, Perlman EJ, et al. Treatment of anaplastic histology Wilms’ tumor: results from the fifth National Wilms’ Tumor Study. J Clin Oncol. 2006;24:2352–2358. 13. Faria P, Beckwith JB, Mishra K, et al. Focal versus diffuse anaplasia in Wilms tumor—new definitions with prognostic significance: a report from the National Wilms Tumor Study Group. Am J Surg Pathol. 1996;20:909–920. 14. Zuppan CW, Beckwith JB, Luckey DW. Anaplasia in unilateral Wilms tumor: a report from the National Wilms’ Tumor Study Pathology Center. Hum Pathol. 1988;19:1199–1209. 15. Beckwith JB, Breslow NE, Faria P, et al. Treatment of children with stages II to IV anaplastic Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol. 1994;12: 2126–2131. 16. Bosnib SM. Non neoplastic disease of the kidney. In: Bostwick DC, Cheng L, eds. Urologic Surgical Pathology. 2nd ed. Philadelphia, PA: MOSBY Elesvier; 2008:1–75. 17. Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet. 1998;79:268–273. 18. Pritchard-Jones K, Gordan M, Vujani GM. Recent developments in the molecular pathology of paediatric renal tumors. Open Pathol J. 2010;4:32–39. 19. Zin RM, Murch A, Carles A. Pathology, genetics and cytogenetics of Wilms’ tumour. Pathology. 2011;43:302–312. 20. Beckwith JB, Kiviat NB, Bonadio JF. Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms’ Tumor. Pediatr Pathol. 1990;10:1–36. 21. Vicens J, Iotti A, Lombardi MG, et al. Diffuse hyperplastic perilobar nephroblastomatosis. Pediatr Dev Pathol. 2009;12: 237–238. 22. Perlman EJ, Faria P, Soares A, et al. Hyperplastic perilobar nephroblastomatosis: long-term survival of 52 patients. Pediatr Blood Cancer. 2006;46:203–221. 23. Hennigar RA, O’Shea PA, Grattan-Smith JD. Features of nephrogenic rests and nephroblastomatosis. Adv Anat Pathol. 2001;8:276–289. 24. Argani P, Collins MH. Anaplastic nephrogenic rest. Am J Surg Pathol. 2006;30:1339–1341. 25. Vuononvirta R, Sebire NJ, Dallosso AR, et al. Perilobar nephrogenic rests are nonobligate molecular genetic precursor lesions of insulin-like growth factor-II-associated Wilms tumors. Clin Cancer Res. 2008;23:7635–7644. 26. Koziell A, Charmandari E, Hindmarsh PC, et al. Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy? Clin Endocrinol (Oxf). 2000;52:519–524. 27. Kreidberg JA, Sariola H, Loring JM, et al. WT-1 is required for early kidney development. Cell. 1993;74:679–691. r

2014 Lippincott Williams & Wilkins

Adv Anat Pathol



Volume 21, Number 3, May 2014

28. Christopher R, Burrow CR. Regulatory molecules in kidney development. Pediatr Nephrol. 2000;14:240–253. 29. Hohenstein P, Hastie ND. The many facets of the Wilms’ tumour gene, WT1. Hum Mol Genet. 2006;15:196–201. 30. Mrowka C, Schedl A. Wilms’ tumor suppressor gene WT1: from structure to renal pathophysiologic features. J Am Soc Nephrol. 2000;11:S106–S115. 31. Segers H, Kersseboom R, Alders M, et al. Frequency of WT1 and 11p15 constitutional aberrations and phenotypic correlation in childhood Wilms tumour patients. Eur J Cancer. 2012;48:3249–3256. 32. Scott RH, Anne Murray A, Baskcomb L, et al. Stratification of Wilms tumor by genetic and epigenetic analysis. Oncotarget. 2012;3:327–335. 33. Satoh Y, Nakadate H, Nakagawachi T, et al. Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms’ tumours. Br J Cancer. 2006;95:541–547. 34. Fukuzawa R, Anaka MR, Heathcott RW, et al. Wilms tumour histology determined by distinct types of precursor lesions and not epigenetic changes. J Pathol. 2008;215:377–387. 35. Haruta M, Arai Y, Watanabe N, et al. Different incidences of epigenetic but not genetic abnormalities between Wilms tumors in Japanese and Caucasian children. Cancer Sci. 2012;103:1129–1135. 36. Fukuzawa R, Reeve AE. Molecular pathology and epidemiology of nephrogenic rests and Wilms tumors. J Pediatr Hematol Oncol. 2007;29:589–594. 37. Jenkins ZA, van Kogelenberg M, Morgan T, et al. Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis. Nat Genet. 2009;41:95–100. 38. Fukuzawa R, Holman SK, Chow CW, et al. WTX mutations can occur both early and late in the pathogenesis of Wilms tumour. J Med Genet. 2010;47:791–794. 39. Wegert J, Wittmann S, Leuschner I, et al. WTX inactivation is a frequent, but late event in Wilms tumors without apparent clinical impact. Chromosomes Cancer. 2009;48:1102–1111. 40. Perotti D, Gamba B, Sardella M, et al. Functional inactivation of the WTX gene is not a frequent event in Wilms’ tumors. Oncogene. 2008;27:4625–4632. 41. Freed-Pastor WA, Prives C. Mutant p53: one name, many proteins. Genes Dev. 2012;26:1268–1286. 42. Bardeesy N, Falkoff D, Petruzzi MJ, et al. Anaplastic Wilms’ tumour, a subtype displaying poor prognosis, harbours p53 gene mutations. Nat Genet. 1994;7:91–97. 43. Jadali F, Sayadpour D, Rakhshan M, et al. Immunohistochemical detection of p53 protein expression as a prognostic factor in Wilms tumor. Iran J Kidney Dis. 2011;5:149–153. 44. Grill C, SunItsch S, Hatz M, et al. Activation of beta-catenin is a late event in the pathogenesis of nephroblastomas and rarely correlated with genetic changes of the APC gene. Pathology. 2011;43:702–706. 45. Maiti S, Alam R, Amos CI, et al. Frequent association of betacatenin and WT1 mutations in Wilms tumors. Cancer Res. 2000;60:6288–6292. 46. Koesters R, Ridder R, Kopp-Schneider A, et al. Mutational activation of the beta-catenin proto-oncogene is a common event in the development of Wilms’ tumors. Cancer Res. 1999;59:3880–3882. 47. Li CM, Kim CE, Margolin AA, et al. CTNNB1 mutations and overexpression of Wnt/beta-catenin target genes in WT1mutant Wilms’ tumors. Am J Pathol. 2004;65:1943–1953. 48. Spreafico F, Gamba B, Mariani L, et al. Loss of heterozygosity. Analysis at different chromosome regions in Wilms

r

2014 Lippincott Williams & Wilkins

Wilms Tumor

49.

50. 51. 52. 53. 54. 55. 56.

57.

58. 59. 60. 61.

62.

63. 64. 65. 66. 67. 68.

tumor confirms 1p allelic Loss as a marker of worse prognosis: a study from the Italian Association of Pediatric Hematology and Oncology. J Urol. 2013;189:260–267. Grundy PE, Breslow NE, Li S, et al. Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol. 2005;23: 7312–7321. Schaub R, Burger A, Bausch D, et al. Array comparative genomic hybridization reveals unbalanced gain of the MYCN region in Wilms tumors. Cancer Genet Cytogenet. 2007;72:61–65. Bhatnagar S. Management of Wilms’ tumor: NWTS vs. SIOP. J Indian Assoc Pediatr Surg. 2009;14:6–14. Ahmed HU, Arya M, Tsiouris A, et al. An update on the management of Wilms’ tumour. Eur J Surg Oncol. 2007;33: 824–831. Vujanic GM, Sandstedt B. The pathology of Wilms’ tumour (nephroblastoma): the International Society of Paediatric Oncology approach. J Clin Pathol. 2010;63:102–109. Kusuma V, Gowda VKS, Geethamani Saini ML. Adult Wilms’ tumour: a case report with review of literature. Diagn Pathol. 2006;1:46. Terenziani M, Spreafico F, Collini P, et al. Adult Wilms’ tumor: a monoinstitutional experience and a review of the literature. Cancer. 2004;101:289–293. Ali AN, Diaz R, Shu HK, et al. A Surveillance, Epidemiology and End Results (SEER) Program comparison of adult and pediatric Wilms’ tumor. Cancer. 2012;118: 2541–2551. Karlsson J, Holmquist Mengelbier L, Elfving P, et al. Highresolution genomic profiling of an adult Wilms’ tumor: evidence for a pathogenesis distinct from corresponding pediatric tumors. Virchows Arch. 2011;459:547–553. Krishnan J, Pietras J, Nachmann M, et al. Adult Wilms’ tumor with a unique presentation of high-grade fever, photophobia, and headache. Rev Urol. 2012;14:31–34. Kilton L, Matthews MJ, Cohen MH. Adult Wilms tumor: a report of prolonged survival and review of literature. J Urol. 1980;124:1–5. Adolphs HD, Kno¨pfle G, Vogel J, et al. Wilms’ tumor in the adolescent and adult. Eur Urol. 1983;9:281–287. Jimenez RE, Folpe AL, Lapham RL, et al. Primary Ewing’s sarcoma/primitive neuroectodermal tumor of the kidney: a clinicopathologic and immunohistochemical analysis of 11 cases. Am J Surg Pathol. 2002;26:320–327. Argani P, Faria PA, Epstein JI, et al. Primary renal synovial sarcoma: molecular and morphologic delineation of an entity previously included among embryonal sarcomas of the kidney. Am J Surg Pathol. 2000;24:1087–1096. Deshpande AV, Gawali JS, Sanghani HH, et al. Extrarenal Wilm’s tumour—a rare entity. Pediatr Surg Int. 2002;18:543–544. Yamamoto T, Nishizawa S, Ogiso Y. Paratesticular extrarenal Wilms’ tumor. Int J Urol. 2012;19:490–491. Rojas Y, Slater BJ, Braverman RM, et al. Extrarenal Wilms tumor: a case report and review of the literature. J Pediatr Surg. 2013;48:E33–E35. Andrews PE, Kelalis PP, Haase GM. Extrarenal Wilms’ tumor: results of the National Wilms’ Tumor Study. J Pediatr Surg. 1992;27:1181–1184. Jia HM, Zhang KR, Shu H, et al. Presacral extrarenal Wilms tumor in a child. Urology. 2009;74:308–310. Aterman K. Extrarenal nephroblastomas. J Cancer Res Clin Oncol. 1989;115:409–417.

www.anatomicpathology.com |

173

Wilms tumor: an update.

Wilms tumor (WT) is the most common neoplasm of the kidney in children. It is an embryologic tumor that histologically mimics renal embryogenesis and ...
998KB Sizes 0 Downloads 4 Views