The Wilm's tumor is one of the great success stories of modern pediatric oncology. By carefully collecting data on both the histology and clinical presentations of these tumors, pathologists enabled oncologists to develop effective chemotherapy regimens. Today, the combination of dactinomycin and vincristine is an effective combination for the treatment of favorable histology tumors.
Wilm's tumor is the most common cancer occurring in the genitourinary tract in children. It may be associated with many medical conditions and thus a careful physical examination is needed to exclude other syndromes. The tumors may present with an abdominal mass. It may be associated with pain, hematuria, hypertension, and even rupture.
Epidemiology Disease Associations Pathogenesis Laboratory/Radiologic/Other Diagnostic Testing Gross Appearance and Clinical Variants Histopathological Features and Variants Special Stains/
Differential Diagnosis Prognosis Treatment Commonly Used Terms Internet Links
EPIDEMIOLOGY CHARACTERIZATION SYNONYMS Nephroblastoma-preferred name INCIDENCE
Most common genitourinary cancer in children accounting for 80% of cases
1-8/10,000 live births in white population
Most common in ages 1-3 years
98% <10 years
Males mean 36.5 months
Females mean 42.5 months
SEX (M:F) Equal GEOGRAPHY
Higher incidence among blacks
Lower incidence among Asians
Incidence not altered by immigration
DISEASE ASSOCIATIONS CHARACTERIZATION Conditions associated with definite increased risk Wilms-Aniridia genital anomaly-retardation (WAGR) syndrome
Conditions associated with possible increased risk Renal malformations
Cutaneous nevi, angiomas
PATHOGENESIS CHARACTERIZATION DCC GENE
Microsatellite analysis of the DCC gene in nephroblastomas: pathologic correlations and prognostic implications.
Ramburan A, Chetty R, Hadley GP, Naidoo R, Govender D.
1Department of Pathology, Nelson R Mandela School of Medicine, University of Natal, Durban, South Africa.
Mod Pathol. 2004 Jan;17(1):89-95 Abstract quote.
Microsatellite instability has been reported in a wide variety of cancer types. Inactivation or loss of tumour suppressor genes has been shown to result in cell cycle deregulation and neoplastic growth.
We conducted a microsatellite study using fluorescent-based DNA technology to determine whether mutations in the microsatellite sequences of the deleted in colorectal cancer (DCC) gene, a tumour suppressor at 18q21.1, have any pathologic correlation or prognostic significance in nephroblastomas. Normal and tumour DNA was isolated from 106 cases of nephroblastoma using the standard proteinase K digestion and phenol-chloroform extraction method from paraffin wax-embedded tissue. Polymerase chain reaction using three microsatellite markers; D18S21, D18S34 and D18S58, for the DCC gene were performed. The polymerase chain reaction products were analysed on the ALF Express Automated DNA sequencer.
The results were correlated with age at diagnosis, preoperative chemotherapy, clinicopathological stage, histological classification and patient outcome using chi(2) test. Allelic imbalance/loss of heterozygosity appeared to be a more frequent genetic aberration than microsatellite instability with 20% of cases showing allelic imbalance/loss of heterozygosity and only 9% of cases showing microsatellite instability. Genetic aberrations were more frequent in unfavourable histology tumours compared to favourable histology tumours (P=0.012). All patients with genetic aberrations for more than one DCC marker died independent of histological classification and stage (P=0.016). There was no statistically significant difference when DCC aberrations were compared with age at diagnosis, preoperative chemotherapy and clinicopathological stage.
In conclusion, this study has found that multiple aberrations involving the DCC locus may play a role in the progression of nephroblastomas, and hence confer a poorer prognosis.
WT1 gene (11p13) Gene encodes for a zinc finger transcription factor expressed in early development of the kidney and genital system WT2 gene
Am J Surg Pathol 2000;24:1663-1669
Adult tumors are rare and thought to have worse prognosis
This genetic change present in 3/5 cases with all tumors diploid for chromosome 12
Follow-up for a median of 82 months found progression in only one patient with stage IV disease
Suggestion that adult cases of Wilm's tumor may be overdiagnosed and most blastema-only tumors in adults are not Wilm's tumor, and in an adult, biphasic morphology should be the minimum criteria for diagnosis
Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilm's tumor.
Beckwith JB, Kiviat NB, Bonadio JF.
Pediatr Pathol 1990;10:1-36
Nephrogenic rests are "a focus of abnormally persistent nephrogenic cells, retaining cells that can be induced to form a Wilms' tumor."
Nephroblastomatosis is defined as "the diffuse or multifocal presence of nephrogenic rests or their recognized derivatives."
These two entities represent a spectrum of the same disease
The classification is further based upon the location of the remnants with relation to the renal lobe:
Perilobar nephrogenic rests-Subcapsular and/or central portions of the columns of Bertin in a mature kidney
Intralobar-Islands lie within the lobe and not at the periphery
Combined-Intra and perilobar nests
Clonality and loss of heterozygosity of WT genes are early events in the pathogenesis of nephroblastomas.
Guertl B, Ratschek M, Harms D, Jaenig U, Leuschner I, Poremba C, Hoefler G.
Institute of Pathology, University of Graz, Graz, Austria; Institute of Pediatric Pathology, University of Kiel, Kiel, Germany; and Gerhard-Domagk-Institute of Pathology, Muenster, Germany.
Hum Pathol 2003 Mar;34(3):278-81 Abstract quote
Nephrogenic rests (NRs), putative precursor lesions of nephroblastomas (Wilms' tumors), are found in 25% to 40% of kidneys presenting with nephroblastomas. Nephroblastomas are clonal tumors that, according to a genetic multistep model, are thought to arise as subclonal proliferations from NRs by accumulating genetic alterations. Different candidate genes for the pathogenesis of nephroblastomas have been identified, including those at chromosomes 11p13 (WT1 gene), 11p15 (WT2 gene), and 16q (WT3 gene).
We investigated clonality and loss of heterozygosity (LOH) at these loci in different subtypes of NR. After microdissection under microscopic control, we analyzed a highly polymorphic locus of the human androgen receptor gene (HUMARA) for nonrandom X-inactivation of genomic DNA using a methylation-sensitive restriction enzyme to investigate clonality. Out of 14 patients, we found that 1 case each of adenomatous and hyperplastic NR and 2 of 7 cases of sclerosing NR were monoclonal. Five patients were noninformative. We assessed LOH at chromosomes 11p13, 11p15, and 16q by analyzing polymorphic gene loci at these regions. One hyperplastic NR and the corresponding tumor showed LOH at 11p13 and 11p15; 1 sclerosing NR and the corresponding tumor exhibited LOH at chromosome 16q.
We demonstrate for the first time that sclerosing NRs can exhibit genetic alterations found in nephroblastomas, namely monoclonality and LOH at the WT gene loci. The histological morphology is no different between NRs with these genetic alterations and NRs without them. We conclude that these genetic changes are early events in the multistep genetic pathogenesis of nephroblastomas; however, they do not seem to fully determine a malignant potential of NR.
Mutations of p53 in Wilms' tumors.
Takeuchi S, Bartram CR, Ludwig R, Royer-Pokora B, Schneider S, Imamura J, Koeffler HP.
Department of Medicine, Cedars-Sinai Medical Center, UCLA School of Medicine 90048, USA.
Mod Pathol 1995 Jun;8(5):483-7 Abstract quote
Mutations of p53 frequently occur in a wide variety of cancers including lung, breast, gastrointestinal, brain, and hematologic malignancies. These alterations apparently contributed to development of the malignant phenotype. Wilms' tumor is one of the most common solid tumors in childhood. The frequency of p53 alterations in this tumor is unknown.
We analyzed 66 Wilms' tumor samples for p53 mutations by single-stand conformational polymorphism (SSCP) following polymerase chain reaction (PCR). Samples with an abnormal SSCP pattern were reamplified and analyzed by direct sequencing method. Mutations of p53 were found in three (5%) of 66 Wilms' tumors within the coding region (exons 2-11), showing that the frequency of p53 mutations was low. Two mutations substituted amino acids residues and one encoded a stop codon. Two of the mutations were located in the mutational hotspots (exons 5 and 6); the other was in exon 10.
These data suggest that p53 mutations are infrequent in the development of Wilms' tumors.
CHARACTERIZATION CT/MRI/Ultrasound All are helpful in identifying the tumor, ultrasound is helpful in identifying cystic component Serum mucin Circulating serum mucin may appear as blue granular material on a peripheral blood smear Acquired von Willebrand factor May be associated with severe coagulopathy
Serum Creatine Kinase Levels Parallel the Clinical Course for Rhabdomyomatous Wilms Tumor
Brett Delahunt, MD, FRCPA
Margaret E. Lewis, MB, ChB, FRCP
Kevin C. Pringle, MB, ChB, FRACS
Esko J. Wiltshire, MB, ChB, FRACP
Michael J. Crooke, PhD, FRCPA
Am J Clin Pathol 2001;116:354-359 Abstract quote
A right-sided renal mass in an 11-month-old girl was diagnosed by percutaneous needle biopsy as Wilms tumor, which on histologic examination was found to be predominantly rhabdomyomatous. As part of the examination, serum creatine kinase (CK) and CK-MB levels were measured and were significantly elevated at 994 U/L (reference range, 42-180 U/L) and 40 U/L (reference range, 0-3 U/L), respectively. Subsequently, an 8-month-old girl was admitted to the hospital with septicemia and was found to have an abdominal mass. A diagnosis of bilateral Wilms tumor was made following percutaneous biopsy of both kidneys; histologic examination confirmed that the tumor was predominantly rhabdomyomatous. Serum CK and CK-MB levels also were measured and were significantly elevated at 685 U/L and 84.4 U/L, respectively.
In both cases, the serum CK and CK-MB levels reflected the clinical course; elevation in serum levels was associated with tumor recurrence, infarction, or chemotherapy-related necrosis.
We conclude that these enzymes have clinical usefulness as markers for Wilms tumor showing rhabdomyomatous morphologic features.
Usually solitary, rounded mass sharply circumscribed from surrounding kidney-may occur anywhere in the kidney
Median 550 grams ranging from 60-6350 grams
Hemorrhage and necrosis common
Bulge from cut surfaces with a uniform pale gray or tan appearance
May be divided by prominent septae or may have polypoid protrusions
Usually demaracated by a dense tumor capsule
Frequently extends into renal vein and metastasizes to the regional lymph nodes
May have extensive permeation of intrarenal blood and lymphatic vessels
Bilateral tumors 5% of cases Multicentric 7% of cases Extra-renal tumors May arise from exophytic growth from a narrow renal pedicle or neoplastic transformation of an afferent branch of the ureteric bud CLINICAL VARIANTS Familial cases 1% of cases have a family history
Probable autosomal dominant inheritance with variable penetrance
Adult Extrarenal Wilms Tumor Occurring in the Uterus A Case Report and Review of the Literature
Ronald S. Muc, BSc, MBBCh(Wits), FCPath(SA), Wayne Grayson, MBChB, FCPath(SA), and Johannes J. Grobbelaar, MBChB, Dipl Obstetrics(SA), FCOG(SA)
From the Department of Anatomical Pathology, School of Pathology, University of the Witwatersrand, and the South African Institute for Medical Research, Johannesburg, Republic of South Africa (Drs Muc and Grayson).
Arch Pathol Lab Med 2001;125:1081–1083. Abstract quote
Five previous cases of extrarenal Wilms tumor (EWT) occurring in the uterus have been reported. The oldest patient was 22 years. We report a case of uterine EWT occurring in a 42-year-old woman. Histologically, there was typical triphasic differentiation, including epithelial, blastemal, and mesenchymal elements. The important differential diagnosis in this age group, the malignant mixed mullerian tumor, is excluded by the absence of glomeruloid structures and primitive tubules.
The exact histogenesis of EWT is unknown but most likely relates to the presence of nephrogenic rests occurring in the female genital tract
HISTOLOGICAL TYPES CHARACTERIZATION General-Favorable Histology
Mixture of cell types differentiating into blastema, epithelium, and stroma
This triphasic pattern is the most common but mono- and bi-phasic tumors are also identified
Blatemal Resembles condensed mesenchyme of the embryonic kidney
Small closely packed and mitotically active cells with minimal differentiation
Diffuse blastemal Large sheets of blastema
May extend beyond kidney and diffusely infiltrative
Serpentine blastemal Frequent pattern with undulating cords of blastemal cells in a loose, myxoid stroma Nodular blastemal Blastemal islands are rounded Basaloid blastemal Serpentine or nodular patterns are outlined in a distinctive epithelial layer Epithelial
Recapitulates various stages of normal nephrogenesis resembling collecting ducts or nephrons and glomeruli
Heterologous elements of mucin, squamous, and ciliated epithelium may occur
Myxoid and spindle cells resembling embryonic mesenchyme
Skeletal muscle most common element
Various elements including cartilage, adipose tissue, bone, mature ganglion cells, and neural tissue
This is the most imporant histologic finding which separates good versus poor prongosis tumors
Anaplasia refers to extreme nuclear atypia rather than lack of cellular differentiation
Observed in 4.5% of cases
Rare in tumors <2 years of age
Increases in prevalenece to 10% by age 6 years
2-3x more common in blacks vs. whites
Diffuse If anaplasia is diffusely distributed throughout the tumor, it is associated with a poor prognosis Focal
Focal anaplasia is the presence of one or a few sharply localized regions in a primary tumor, the majority of which contain no nuclear atypia-these changes must be confined to intrarenal tumor sites
No effect on prognosis
Histologic Definition of Anaplasia Multipolar mitotic figures Each component of the mitotic figure should be as large or larger than a normal appearing metaphase Marked nuclear enlargement
Major dimension of affected nuclei at least 3 times that of apparently nonanaplastic nuclei in other areas of the specimen
Should involve all diameters of the nucleus
OTHER HISTOLOGIC CHANGES Foci of renal cell carcinoma Rare
If carcinomatous regions are of high cytologic grade, confer aggressive behavior and poor prognosis similar to high-grade carcinoma in adults
CHARACTERIZATION An Immunophenotypic Comparison of Metanephric Metaplasia of Bowman Capsular Epithelium With Metanephric Adenoma, Wilms Tumor, and Renal DevelopmentA Case Report and Review of the Literature
Edgar G. Fischer, MD, PhD, etal.
Am J Clin Pathol 2004;121:850-856 Abstract quote
Metanephric metaplasia of the parietal epithelium of the Bowman capsule is a rare pathologic finding of unknown pathogenesis that has occurred in patients with widespread malignant neoplasms of various types.
We report this finding in a 25-year-old woman with partial expression of the Carney triad who died of a disseminated gastrointestinal stromal tumor, specifically a gastric stromal sarcoma. The metaplasia involved both kidneys diffusely. It originated in the parietal epithelium of the Bowman capsule, extended into the proximal tubules, and focally surrounded the glomeruli in a semicircular manner.
Immunohistochemical analysis revealed that the cells of metanephric metaplasia expressed the Wilms tumor gene product, bcl-2 protein, and CD57 and cytokeratin 7 and keratin AE1/AE3 focally, but not CD56. This immunophenotype parallels that of metanephric adenoma, Wilms tumor, and nephrogenic rests and overlaps with antigen expression in certain periods of renal development.
The Expression of WT1 in the Differentiation of Rhabdomyosarcoma from Other Pediatric Small Round Blue Cell Tumors.
Carpentieri DF, Nichols K, Chou PM, Matthews M, Pawel B, Huff D.
Departments of Pathology (DFC, MM, BP, DH) and Oncology (KN), The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.
Mod Pathol 2002 Oct;15(10):1080-6 Abstract quote
The WT1 gene encodes a transcription factor implicated in normal and neoplastic development.
The purpose of this study was to evaluate the diagnostic utility of a commercial WT1 antibody on a variety of pediatric small round blue cell tumors (SRBCT). A mouse monoclonal antibody (clone: 6F-H2, DAKO) raised against the N-terminal amino acids 1-181 of the human WT1 protein was tested. Microscopic sections from 66 specimens were stained using an antigen retrieval protocol with trypsin. The tumors included peripheral neuroectodermal tumors (PNET/Ewing's), neuroblastomas, desmoplastic small round cell tumors (DSRCT), lymphomas, Wilms' tumors, and rhabdomyosarcomas (RMS). One RMS case was investigated by Western blot analysis and RT-PCR to confirm the antibody specificity. A strong cytoplasmic staining was demonstrated in all RMS (11/11).
The Western blot analysis confirmed the WT1 protein in the tissue, and the RT-PCR confirmed the presence of WT1 mRNA in the peripheral blood and tissue of one RMS patient. The Wilms' tumors had a variable nuclear and/or cytoplasmic positivity in most (17/24) cases. All PNET/Ewing's were negative. The nuclei of two lymphoblastic lymphomas stained strongly. A weak nuclear or cytoplasmic staining was reported in a few DSRCT (3/5), lymphomas (2/10), and neuroblastomas (2/8).
This is a useful antibody in the differentiation of RMS from other SRBCTs. A strong cytoplasmic staining favors an RMS, and a strong nuclear staining is suggestive of a Wilms' tumor. A role for WT1 in the pathogenesis of rhabdomyosarcomas is raised. The limited sampling precludes any conclusions regarding the value of tissue or peripheral blood analysis for WT1 mRNA in patients with rhabdomyosarcoma.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES NEOPLASM ESTIMATED RELATIVE FREQUENCY % Wilm's Tumor-nonanaplastic 80 Wilm's Tumor-anaplastic 5 Mesoblastic nephroma 5 Clear cell sarcoma 4 Rhabdoid tumor 2
4 NEPHROGENIC RESTS
- Lumbosacral Ectopic Nephrogenic Rest Unassociated With Spinal Dysraphism.
Horenstein MG, Manci EA, Walker AB, Dehner LP.
Departments of *Pathology and daggerSurgery, University of South Alabama College of Medicine and Medical Center, Mobile, AL; and the double daggerDepartments of Pathology and Immunology, Washington University School of Medicine and Medical Center, St. Louis, MO.
Am J Surg Pathol. 2004 Oct;28(10):1389-1392. Abstract quote
Nephrogenic rests (NRs) are thought to originate from persistent nephrogenic blastema and are considered precursor lesions of Wilmsâ€™ tumor (WT). These rests usually occur as perilobar and intralobar lesions in the kidney and, rarely, in ectopic sites.
We report a midline lumbosacral ectopic NR in a healthy full-term newborn male with no family history of WT or WT-associated syndromes. The NR presented as a soft polypoid mass covered by normal skin. An MRI study revealed no lumbosacral spine abnormalities and no communication with the vertebral canal. The resected mass measured 3 cm and contained fat and had a central 1.2-cm solid nodule. The nodule was composed of blastema, epithelial elements (mature tubules and nephrons), and abundant stroma. No other somatic tissue elements were identified after complete microscopic examination. There are 4 cases of NRs reported in the lumbosacral area associated with spinal dysraphism, and only 2 cases, in addition to our report, unassociated with spinal abnormalities.
The pathogenesis of heterotopic immature nephrogenic tissue remains a source of conjecture and speculation. If these lesions are heterotopic rests, their potential for neoplastic progression is probably quite limited, but if a monodermal teratoma, then more scrupulous clinical follow-up is warranted.
PROGNOSIS AND TREATMENT CHARACTERIZATION Prognostic Factors
Significant poor prognostic factors:
Advanced age at detection
Nephroblastoma: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells.
Camassei FD, Arancia G, Cianfriglia M, Bosman C, Francalanci P, Rava L, Jenkner A, Donfrancesco A, Boldrini R.
Department of Pathology, Bambino Gesu Children's Hospital-Research Institute, Rome, Italy.
Am J Clin Pathol 2002 Mar;117(3):484-90 Abstract quote
The development of chemoresistance in a variety of cancers seems related to overexpression of the P-glycoprotein (P-gp) drug pump. Nephroblastoma, the most common malignant renal tumor of childhood, usually is responsive to treatment, and prognosis is favorable in most cases. However, the disease in a subset of patients is refractory to treatment, and the disease follows an aggressive course.
To study P-gp expression in this tumor and its correlation with outcome, tumor samples from 93 patients were examined by immunohistochemical analysis. P-gp expression was determined separately in both tumor cells and intratumoral capillary endothelium. The likelihood ratio test, the Kaplan-Meier method, and the log-rank test were used to evaluate its association with clinical course, grade, stage, and administration of preoperative chemotherapy. The results for the majority of nephroblastomas were variably positive; in 43 (46%) of them, newly formed capillary endothelial cells also stained positive.
While no association of P-gp expression in tumor cells with clinical course, stage, and grade could be demonstrated, positivity in endothelial cells correlated significantly with unfavorable outcome, suggesting that chemoresistance depended on an active blood-tumor barrier. Previous chemotherapy induced P-gp overexpression in tumor cells.
STAGING OF PEDIATRIC RENAL TUMORS (NWTS) DEFINTION I-Limited to kidney and completely resected Renal capsule intact
Renal sinus may be infiltrated but not beyond the hilar plane
II-Tumor infiltrates beyond kidney, but completely resected Includes cases with tumor penetration of renal capsule or infiltration of renal vessels beyond the hilar plane, biopsied tumors, and those with local spillage confined to the flank
Simple protrusion of the tumor beyond the capsule or hilar plane is acceptable for stage I designation
III-Residual nonhematogenous tumor confined to abdomen
Includes cases with one of the following:
Tumor in abdominal lymph nodes
Diffuse peritoneal contamination by direct tumor growth, tumor implants, or spillage into peritoneum before or during surgery
Involvement of specimen margins grossly or microscopically
Residual tumor in abdomen
IV-Hematogenous metastases V-Bilateral renal involvement at diagnosis Tumors in each kidney should be separately substaged in each case 5 Year Survival Majority of tumors are low stage and have favorable histology Metastasis
Regional lymph nodes, lungs, and liver
Rupture of the tumor may lead to peritoneal implants
TREATMENT Combination of dactinomycin and vincristine Stage I and II-Favorable histology Chemotherapy Stage I-Unfavorable histology Chemotherapy Stage II-IV Unfavorable histology Chemotherapy with adjuvant agents and radiotherapy
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Metanephric Stromal Tumors
National Wilms Tumor Study (NWTS)-A national registry of patients with the tumor. Epidemiologic, pathologic, and clinical data are collected on all cases.
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Last Updated October 7, 2004
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