Wilms tumor and von Hippel Lindau disease

Introduction

Nephroblastoma, or Wilms tumor (WT), is the most common primary renal malignancy in childhood and represents 6% of all childhood cancers. WTs comprise over 95% of all kidney tumors in children younger than 15 years old. ^, Usually found in children 1 to 5 years old, the tumor is still a rare finding. Overall, the incidence of WT is 1 in 10,000 children under 5 years of age and only 7 per million children under age 15 years. ^, The Children’s Oncology Group (COG) reports that in the United States, roughly 600 children are diagnosed with a primary renal tumor each year and that over 90% of these are WTs.

Named for Max Wilms, the disease is characterized by the presence of an embryonal tumor derived from the metanephros. Although historically a death sentence, WT is one of the greatest success stories of modern medicine: survival rates rose from less than 5% in 1900 to over 90% in modern times. The increased survival is the result of both improved diagnosis and identification, in addition to better surgical and chemotherapeutic approaches. Much of this improvement in outcomes is attributable to large research organizations, such as the Children’s Cancer Group, Société Internationale d’Oncologie Pédiatrique (SIOP), and the National Wilms’ Tumor Study Group (NWTS) (replaced by the renal tumor section of the COG) in 2001. For decades, these organizations have collected systematic databases for analysis and have supported large controlled treatment trials. This chapter will review the presentation, diagnosis, treatment, and outcomes of WT.

Diagnosis and histology

Nephroblastoma usually presents as a single kidney nodule, although multifocal unilateral or even bilateral tumors are possible. Bilateral tumors typically account for only 5% to 7% of all diagnosed WT. Clinical presentation may include hematuria or abdominal pain and roughly a quarter (25%) of patients present with hypertension. Grossly, WTs are often large masses, which can vary greatly in size ( Fig. 26.1 ). By the time they are diagnosed, tumors usually disrupt renal architecture. Typical histology includes blastemal, epithelial, and stromal tissue, although the proportion of each tissue type varies considerably between tumors. It is rare to see the classic histologic triad, and biphasic or even monophasic tumors are not uncommon.

When epithelial tissue predominates, differential diagnosis includes renal cell carcinoma (RCC) (rare in childhood), metanephric adenoma, or hyperplastic nephrogenic rest. Pure blastemal tumors, the least differentiated and likely most malignant, may resemble other types of embryonal “small round blue cell” tumors, such as neuroblastoma, desmoplastic small round cell tumor, primitive neuroectodermal tumor (PNET), and even lymphoma. There are several patterns of blastemal tumor growth, including serpentine, diffuse, nodular, and basaloid.

Histopathology

Predisposing nephrogenic rests are areas of embryonal tissue of metanephric origin still present after 36-weeks’ gestation. Only rarely will these nephrogenic rests develop clonal expansion to become malignant WTs. Up to 30% of patients with sporadic WT will have nephrogenic rests, although they are found in well over 90% of patients with multifocal or bilateral disease. The presence of multiple nephrogenic rests is referred to as nephroblastomatosis . WTs present with classic triphasic histopathologic components: blastemal, epithelial, and stromal. The proportion and degree of differentiation of these cell types is widely variant, such that each tumor is histologically unique. This significant histologic heterogeneity can make diagnosis challenging for pathologists. Nonetheless, morphologic appearance of WT is critical to appropriate staging and risk stratification. The blastemal cells are tightly packed with small, round nuclei and little cytoplasm ( Fig. 26.2 ). Blastemal-predominant tumors, among the “small round blue cell” tumors, may be difficult to distinguish from neuroblastoma, PNET, and desmosplastic small round cell tumors. These blastemal WTs are more aggressive and have a poorer outcome. In addition to blastemal type, WTs with diffuse anaplasia are considered “high risk” and are more aggressively treated (see later). The epithelial component is heterogeneously differentiated from normal appearing glomeruli to poorly defined tubules. In contrast, the stromal component resembles anything from immature fibroblasts to muscle or neural tissue. There may be spindle cells (mesenchymal embryo) with myxoid cytoplasm.

Although classic triphasic WT is relatively easy to identify, many tumors are biphasic or monophasic in appearance. Additional challenges to accurate diagnosis may also be introduced with preoperative chemotherapy, a cornerstone of SIOP treatment regimens. Because of this, there are separate classification schemes for pre- and postchemotherapy appearance.

Blastemas represent the least differentiated tumors and are considered the most malignant. Histologic patterns of blastemal WT include diffuse, nodular, serpentine, and basaloid. All four of these patterns may be present within the same tumor and pattern does not appear to affect prognosis. Diffusely growing blastemal WT may show significant infiltration and lack a pseudocapsule between affected and healthy kidney. Although these tumors may be aggressive, blastemal predominant tumors are usually considered “favorable histology” unless viable blastemal cells persist post standard chemotherapy (in the SIOP regimen).

Epithelial tumors also have a myriad of histologic presentations, from highly differentiated to primitive. These tumors may appear as nests of primitive rosette-like cells to fully formed tubules or glomeruli. Epithelial predominant tumors are also considered lower risk and thus “favorable histology.”

Stromal tumors consist of mesenchymal cells and loose myxoid areas. As with the epithelial component, cells may appear with heterogeneous differentiation, including muscle, cartilage, fat, or even bone tissue. These stromal structures, particularly, are greatly affected by preoperative chemotherapy. These chemotherapy-induced changes (CIC) include necrosis, fibrosis, or bleeding. Frustratingly, the classification of WT is not standard between the many pediatric oncology research groups. SIOP and COG each has a unique criterion, which are described later ( Table 26.1 and Box 26.1 ).

Anaplasia, either focal or diffuse, is found in up to 10% of WTs. This finding has both prognostic and treatment implications and identification of this pathologic entity is critical. As the presence of anaplastic tumor is strongly associated with recurrent disease, patients with anaplasia are referred to as having “unfavorable histology.” Anaplasia is characterized by: (1) enlarged nuclei; (2) heterochromatic nuclei; and (3) multipolar mitotic figures. Patients with anaplastic tumors are often treated more aggressively.

Genetics of wilms

Much work has been done on genetics of WT and the field continues to advance rapidly. First cloned in 1990, WT1 at 11p13 was the first tumor suppressor gene identified in WT. The WT1 gene encodes a 55 kDa zinc finger transcription factor that helps control deoxyribonucleic acid (DNA) binding. The gene may also regulate posttranscription gene expression through messenger ribonucleic acid binding. With 10 exon regions, there are multiple splicing events that are disrupted. The WT1 gene is mutated in up to 12% of WTs. Other genes, such as CTNNB1 (15%) and WTX (18%), have also been identified. CTNNB1 on 3p21 encodes an 88 kDa beta-catenin protein heavily involved in Wnt/beta-catenin signaling pathway. In WT, mutated beta-catenin is found in approximately 15% of tumors.

WT on the X, also referred to as WTX , refers to mutations located on Xq11.1. This gene contributes to stabilization of beta-catenin and acts as a tumor suppressor independent of the Wnt signaling pathway and WTX inactivation has recently been found in up to 30% of WT pathology specimens.

Taken together, genetic variations in one of these three genes ( WT1 , CTNNB1 , and WTX ) is found in up to one-third of the cases of WT. ^, In addition to these genes that are associated with the presence of WT, there are other genes that are markers of outcome. Disease progression in WT has been associated with expression of several genes, including TP53 , MYCN , CITED1 , SIX2 , TOP2A , and CRABP2 . These genes are involved in renal development, chromatin remodeling, DNA methylation, and other cellular functions. Mutations in p53 is the most frequent finding in human malignancy. Located on 17p13.1, the gene encodes TP53, a protein involved in many cellular events, such as DNA repair, apoptosis, and differentiation/proliferation. p53 in WT is associated with relapse, progression, anaplasia, and metastasis. Up to 75% of anaplastic WTs have been reported to have p53 mutations.

Interestingly, not all of the genetic changes seen in WT are the result of genetic mutations. Large scale loss of heterozygosity (LOH) was the first aberration identified. LOH is a common finding in many types of cancer. Even when there exists the genetic loss of one allele, the remaining unaffected allele is able to “cover” protein synthesis and hide the defect. If some second “hit” damages or alters the function of this other allele, then a recessive trait, often a tumor suppressor, becomes manifest. This LOH can be the result of mitotic errors, gene conversion, faulty DNA repair or replication, or some other mishap. LOH for 1p and 16q was identified more frequently among subjects with adverse outcomes in the NWTS-4 trial. Given these findings of worse outcome with these genetic findings, COG uses these LOH markers as a molecular marker for risk stratification. In recent COG protocols, patients having double positive tumors receive increased treatment intensity.

Epidemiology

First described by Max Wilms in 1899, WTs are one of the most common solid tumors in childhood. It is currently the third most common malignancy in children. WT comprises 95% of all renal cancers among children younger than 15 years old. The disease affects approximately 1 in 10,000 children and its incidence is 7 per million and there are roughly 600 children newly diagnosed annually in the United States. WT is usually a sporadic disease, although family history is present in up to 2% of cases. Approximately 10% of WTs are related to germline mutations or other congenital abnormalities that result in a syndromic inheritance (see later).

WT is the second most common solid abdominal tumor (behind neuroblastoma) in children. The mean age at diagnosis is just 3 years old. Presentation is usually an asymptomatic mass detected by parents, primary care providers, or more recently, incidentally found on abdominal imaging.