Renal Tumors

Conrad V. Fernandez

James I. Geller

Peter F. Ehrlich

Ashley D. Hill

John A. Kalapurakal

Jeffrey S. Dome

INTRODUCTION

The kidney is the site of approximately 7% of childhood malignancies including nephroblastoma (Wilms tumor [WT]), clear-cell sarcoma of the kidney (CCSK), malignant rhabdoid tumor (MRT), renal cell carcinoma (RCC), and congenital mesoblastic nephroma (CMN).WT is an exemplar for the multimodal treatment of pediatric solid tumors. Improvements in surgical techniques and postoperative care, recognition of the sensitivity of WT to irradiation, and the availability of active chemotherapeutic agents have led to a dramatic change in the prognosis for this once uniformly lethal malignancy. This chapter reviews the epidemiology, molecular biology, pathology, treatment, and prognosis of children with WT and other pediatric renal cancers.

EPIDEMIOLOGY

The incidence of renal tumors in the United States is 7.1 cases per million children under age 15 years. The total national incidence has been estimated at 600 cases per year on the basis of enrollment on the current Children’s Oncology Group (COG) renal tumor biology and classification study. The vast majority of pediatric renal tumors are WT, but RCC surpasses WT as the most common renal malignancy in the 15- to 19-year age group.¹

The incidence rate for WT is slightly higher for black populations, but substantially lower in Asians.² The male:female ratio is 0.92:1.00 for those with unilateral disease and 0.60:1.00 for those with bilateral disease.² The tumor presents at an earlier age among boys, with the mean age at diagnosis for those with unilateral disease being 41.5 months compared with 46.9 months among girls. The mean age at diagnosis for those who present with bilateral disease is 29.5 months for boys and 32.6 months for girls.²

Approximately 10% of children with WT have congenital anomalies, either isolated or as part of a congenital malformation syndrome. Table 29.1 lists syndromes that are convincingly associated with WT.³ WT also has been reported in other syndromes such as neurofibromatosis type I, Down syndrome, and Marfan syndrome, but these are likely to be sporadic.³ A recent systematic review of 37 studies found significantly increased risk of WT with antenatal maternal exposure to pesticides, high birthweight, and preterm birth.⁴

GENETICS AND MOLECULAR BIOLOGY

Although WT was initially presented as one of the paradigms for Knudson’s two-hit hypothesis,⁵ it is now clear that the development of WT is more complex than the loss of function of a single gene. The three predominant genetic and epigenetic alterations observed in WT are (1) WT1 loss, (2) WNT pathway activation, and (3) IGF2 overexpression. Comprehensive gene expression, mutation, and methylation analysis have identified distinct biological subsets of WT.⁶^,⁷ One model divides WT into five subsets by virtue of their gene expression profiles, as summarized in Table 29.2.⁶ Most WT belong to Subset 5 and demonstrate evidence of IGF2 overexpression without evidence of WNT activation or WT1 loss. Subsets 2, 3, and 4 include tumors with alterations of more than one pathway. Subset 1 tumors lack evidence of WT1 loss, WNT activation, or IGF2 overexpression. The genetic etiology of Subset 1 tumors remains to be determined.

WT1

The discovery of the WT1 gene resulted from the observation that individuals with the syndrome of aniridia, genitourinary anomalies, and mental retardation (WAGR syndrome) are at high risk (>30%) for developing WT. Children with the WAGR syndrome were shown to have heterozygous germline deletions at chromosome 11p13, which were later found to encompass a contiguous set of genes including PAX6, the gene responsible for aniridia, and WT1.⁸^,⁹

The WT1 protein is a transcription factor that regulates expression of genes involved in cell growth, differentiation, and apoptosis.¹⁰ However, it remains unclear which putative targets are functionally important for Wilms tumorigenesis. In most respects, WT1 is a classic tumor suppressor gene, requiring the loss of both alleles for tumor development, but specific alterations to only one allele may contribute to abnormal cell growth. Patients with the Denys-Drash syndrome, which is defined by pseudohermaphroditism, early renal failure with diffuse mesangial sclerosis, and a very high risk of WT (>90%), harbor constitutional point mutations in only one WT1 allele. The abnormal protein product is thought to disrupt the function of the normal gene product (from the remaining normal allele) through the formation of protein complexes or through abnormal interactions with DNA targets. Although mutation of a single WT1 allele is sufficient to produce the abnormal genitourinary effects of Denys-Drash syndrome, biallelic WT1 mutation is required for tumor formation.

The incidence of WT1 mutations in tumor tissue of sporadic WT is 10% to 20%.¹¹ Approximately 2% of patients with sporadic WT without genitourinary anomalies harbor constitutional WT1 mutations, arguing against routine WT1 mutation analysis in such patients.¹²

WNT Signaling Pathway

Activating mutations of CTNNB1, coding for the β-catenin protein, the central effector of the WNT signaling pathway,¹³ have been identified in about 15% of WTs.¹⁴ CTNNB1 mutations are rarely found in the absence of WT1 mutations, suggesting a cooperative effect between these two pathways in the development of WT. WTX (also known as AMER1 and FAM123B) was first reported in 2007 by Haber’s group, which observed 15 of 51 WTs with inactivation of WTX.¹⁵ The mechanism of inactivation mainly involved whole-gene deletion or truncating mutations on the only allele present in males and on the active allele in females. Constitutional WTX mutations are the cause of the rare familial condition osteopathia striata congenita with cranial sclerosis, though all WTX deletions reported in WT have been somatic.¹⁶ WTX inhibits the WNT pathway¹⁷ by interacting directly with β-catenin to promote ubiquitination and degradation.¹⁸ In
the absence of WTX, β-catenin fails to be phosphorylated, is stabilized, and accumulates in the nucleus, where it forms a complex with the Lef-1/TCF family of transcription factors to promote expression of growth-related genes.¹⁹

TABLE 29.1 Syndromes Associated with WT

Syndrome	Locus	Genetic Lesion	Phenotype	Estimated WT Risk
WAGR	11p13	Deletion of WT1 gene	Aniridia, genitourinary anomalies, delayed-onset renal failure	30%
Denys-Drash	11p13	Point mutation in zinc-finger region of WT1 gene	Ambiguous genitalia, diffuse mesangial sclerosis	>90%
Frasier	11p13	Point mutation in WT1 intron 9 donor splice site	Ambiguous genitalia, streak gonads, focal segmental glomerulosclerosis	8%
Beckwith-Wiedemann/Isolated Hemihypertrophy	11p15	Mutation or epigenetic dysregulation of IGF2, H19, KCNQ1 (KvLQT1), KCNQ1OT1 (LIT1), or CDKN1C (p57^KIP2); WT predisposition is confined to patients with IGF2 alterations	Organomegaly, large birthweight, macroglossia, omphalocele, hemihypertrophy, ear pits and creases, neonatal hypoglycemia	5%
Simpson-Golabi-Behmel	Xq26	GPC3 mutations	Overgrowth, course facial features	10%
Li-Fraumeni	17p13	TP53 mutations	Familial predisposition to cancer	Low, but several cases reported
Mosaic variegated aneuploidy	15q15	BUB1B mutations	Microcephaly, growth retardation, developmental delay, cataracts, heart defects	25%
Fanconi anemia D1	13q12	BRCA2 mutations	Short stature, radial ray defects, bone marrow failure	20%
Hyperparathyroid-jaw tumor	1q25-q31	HRPT2 mutations	Fibro-osseous lesions of jaw, parathyroid tumors	Low, but several cases reported
Bloom	15q26	BLM mutations	Short stature, photosensitivity, characteristic facial features	3%
Perlman	2q37	DIS3L2 mutations	Prenatal overgrowth, facial dysmorphism, developmental delay, cryptorchidism, renal dysplasia	33%
Mulibrey Nanism	17q22-23	TRIM37 mutations	Short stature, distinct facial appearance, pericardial constriction, yellow dots in retina, hepatomegaly	<3%
DICER1 predisposition syndrome	14q	DICER1 mutations	Predisposition to pleuropulmonary blastoma, CN, ovarian Sertoli-Leydig cell tumors, intraocular medulloepithelioma, thyroid cysts	Low, but several cases reported
Trisomy 18	18	?	Multiple congenital anomalies	Low, but several cases reported
Trisomy 13	13	?	Multiple congenital anomalies	Low, but two cases reported
2q37 deletion	2q37	Possible miR-562 deletion	Developmental delay, dysmorphic facies, skeletal abnormalities, heart defects	3%

IGF2

The existence of a second WT gene on chromosome 11p (termed “WT2”) was appreciated by the association between WT and Beckwith-Wiedemann syndrome (BWS), a syndrome characterized by overgrowth (hemihypertrophy, visceromegaly, macroglossia) and a predisposition to embryonal tumors.²⁰ BWS results from aberrations at one of several different loci within 11p15, which may be divided into two clusters of imprinted genes, imprinting center 1 (IC1) and imprinting center 2 (IC2). Recent evidence indicates that WTs are initiated by changes confined to IC1, the site of the IGF2 and H19 genes.²¹^,²² IGF2 encodes an embryonal growth factor that is highly expressed in fetal kidney, whereas H19 encodes a biologically active untranslated RNA that may function as a tumor suppressor. In normal cells, these genes are oppositely expressed such that IGF2 is expressed only from the paternal allele and H19 is expressed only from the maternal allele. Among the genes at the 11p15 locus, IGF2 overexpression is thought to be the key inciting factor for WT development. Two primary mechanisms lead to IGF2 overexpression in WT: uniparental isodisomy, duplication of the paternally derived chromosome, which is detected as LOH, and loss of imprinting (LOI) caused by hypermethylation of IC1 (Table 29.2).⁶^,⁷

Familial WT

Familial predisposition to WT is rare and accounts for only 1% to 2% of all cases.²³ In view of the absence of parental consanguinity
in such families, the mode of inheritance is generally thought to be autosomal dominant, with variable penetrance and expressivity.²⁴ Only one-tenth of the kindreds reported involve affected parents.²³ More often, the disease occurs in siblings, cousins, or other relatives. A survey of 191 children of 99 patients with unilateral WT did not identify a single case of cancer.²⁵

TABLE 29.2 Biologically Defined Subsets of WT

	Subset 1	Subset 2	Subset 3	Subset 4	Subset 5
Percentage of WTs	6	12	9	4	71
Histologic features	Epithelial; 0% skeletal muscle	Mixed; 87% skeletal muscle	Mixed; 38% skeletal muscle	Mixed; 60% skeletal muscle	Variable; 17% skeletal muscle
Nephrogenic rests	None	74% ILNR 0% PLNR	76% ILNR 0% PLNR	30% ILNR 0% PLNR	15% ILNR 25% PLNR
Median age (mo)	14	13	39	38	43.5
Relapse (%)^a	0	3	11	16	13
WT1 mutation (%)	0	54	52	10	ND; high WT1 gene expression observed
CTNNB1 exon 3 mutation (%)	0	55	33	20	ND; WNT activation not observed by gene expression profiling
WTX mutation (%)	0	22	24	10	ND; WNT activation not observed by gene expression profiling
11p15 LOH (%)	0	63.5	33.3	50	37.2
11p15 LOI (%)	9	4.5	19.1	30	43.8
Proposed embryonal cell of origin	Postinduction early nephron	Intermediate mesoderm	Metanephric mesenchyme	Intermediate mesoderm	Metanephric mesenchyme
^aStudy was enriched for relapse samples, and these percentages correct for the enrichment.
ND, not determined.

Although constitutional WT1 mutations have been implicated in a few WT families,¹² genetic linkage analysis excluded 11p13 as the predisposing locus in many other affected families. Analysis of two families revealed linkage with chromosome 17q and the putative WT gene at this locus has been named FWT1.²⁶ A second locus, FWT2, has been mapped to chromosome 19q13.3-q13.4.²⁴ The specific genes at the FWT1 and FWT2 loci have yet to be identified. Rare families with WT have been described with biallelic BRCA2 mutations without the expected Fanconi anemia phenotype.²⁷

TP53

WT is a rare component of the Li-Fraumeni syndrome, which is associated with constitutional TP53 mutations. Somatic TP53 mutations are rare in WT of favorable histology, but are detected in approximately 75% of WT with anaplastic histology.²⁸ Microdissection analysis of tumors containing both histologic subtypes indicated that TP53 mutations were restricted to areas of anaplasia, suggesting that acquisition of TP53 mutations is inherent to the process of anaplastic progression.

PATHOLOGY

Gross Appearance and Patterns of Extension

WT tissue is typically pale tan, soft, and friable, and easily spread upon capsular rupture or during gross dissection. Hemorrhage and necrosis frequently impart a variegated appearance. Not uncommonly, especially in infants, a polypoid extension into the pyelocalyceal lumen may resemble the growth pattern seen in botryoid rhabdomyosarcoma. WTs are usually sharply demarcated from the adjacent renal parenchyma, separated by a fibrous pseudocapsule. This fibrous pseudocapsule may be the only feature to distinguish WT from a hyperplastic nephrogenic rest. In addition, because CMN, CCSK, MRT, and renal lymphoma all demonstrate infiltrative borders, the presence of a fibrous pseudocapsule can indicate the correct diagnosis on gross examination. WTs not infrequently involve the renal vein, and may extend up the inferior vena cava (IVC) to reach the right atrium.

Histology

The classic nephroblastoma is made up of varying proportions of three patterns, blastemal, stromal, and epithelial, often recapitulating various stages of normal renal development (Fig. 29.1). Blastemal cells are undifferentiated small blue cells that may be arranged in diffuse or organoid patterns. Epithelial structures such as glomeruli and tubules simulating the normal nephrogenic zone are commonly seen. Less commonly, papillary formations or heterologous squamous or mucinous epithelium unlike any in the normal developing kidney are identified. Stromal differentiation is usually manifest as immature spindled cells, heterologous skeletal muscle, cartilage, osteoid, or fat. Tumors that exhibit exclusively one pattern can present diagnostic difficulties. Monophasic blastemal WTs are often highly invasive and may raise the differential diagnosis of other small round blue cell tumors, such as primitive neuroectodermal tumor, neuroblastoma, and lymphoma. Similarly, monophasic undifferentiated stromal WTs may simulate primary sarcomas such as CCSK, CMN, or synovial sarcoma. Other stromal WTs show a predominance of skeletal muscle differentiation varying from well-differentiated (rhabdomyomatous) to poorly differentiated skeletal muscle (rhabdomyoblastic). The
distinction of a pure rhabdomyoblastic WT (which is quite rare) from a primary renal rhabdomyosarcoma is often impossible on morphologic grounds. Finally, purely tubular and papillary WT may at times be difficult to distinguish from metanephric adenoma and papillary RCC.

Figure 29.1 Triphasic WT, with well-defined tubules emerging from dense clusters of cohesive blastemal cells. Zones of pink-staining stromal differentiation separate blastemal nodules (H & E 100×).

WTs often contain scattered cysts and, not uncommonly, tumors may be predominantly or purely cystic. Those that have grossly identifiable solid nodules of tumor are best classified as cystic WTs. Tumors that are devoid of any solid nodular growth but that contain immature nephrogenic elements within their septa are designated cystic partially differentiated nephroblastoma (CPDN). Others contain only mature cell types and are classified as cystic nephroma (CN). CPDN and CN are both curable by surgery alone, and had been thought to represent the most favorable end of the WT spectrum.²⁹^,³⁰ A familial association between CN and the often cystic pleuropulmonary blastoma (PPB) has been reported.³¹ A recent study of CN and CPDN suggests that these two lesions are genetically distinct from each other, with mutations in DICER1 commonly associated with CN but not CPDN.³² From that study it is also apparent that there is a small risk for malignant progression of CN to high-grade multipatterned sarcoma, resembling progression of cystic to solid PPB. Of note, individuals with the DICER1 cancer predisposition syndrome and WT have been described, as have rare sporadic WT with DICER1 mutations (Table 29.1).³³^,³⁴

A correlation between the histologic pattern and the clinical behavior of WT has long been sought. The most significant predictor of outcome is the presence of anaplastic nuclear changes, as described below. Other more limited correlations between behavior and histology have been reported. Blastemal-rich tumors tend to be invasive and present at a high stage, but often respond well to chemotherapy. In contrast, predominantly epithelial and rhabdomyomatous WTs more frequently present at a low stage, reflecting less aggressiveness, yet are often resistant to chemotherapy. The International Society of Pediatric Oncology (SIOP) protocols administer 4 weeks of chemotherapy before the primary WT is resected, allowing pathologists to develop a histologic grading system that reflects postchemotherapy changes (Table 29.3).

TABLE 29.3 The Revised SIOP Working Classification of Renal Tumors

Risk Category	With Preoperative Chemotherapy	With Primary Nephrectomy
Low-risk tumors	• Mesoblastic nephroma • CPDN • Complete necrosis—nephroblastoma	• Mesoblastic nephroma • CPDN
Intermediate-risk tumors	• Nephroblastoma—epithelial • Nephroblastoma—stromal • Nephroblastoma—mixed • Nephroblastoma—regressive • Nephroblastoma—focal anaplasia	• Nonanaplastic nephroblastoma and its variants • Nephroblastoma—focal anaplasia
High-risk tumors	• Nephroblastoma—blastemal type • Nephroblastoma—diffuse anaplasia • Clear-cell sarcoma kidney • Rhabdoid tumor kidney	• Nephroblastoma—diffuse anaplasia • CCSK • Rhabdoid tumor of the kidney

Anaplastic WT

Anaplasia is defined by the presence of markedly enlarged polyploid nuclei within the tumor sample (Fig. 29.2). The criteria for the diagnosis of anaplasia include (1) the identification of nuclei with a diameter at least 3 times those of adjacent cells; (2) hyperchromasia of the enlarged cells providing evidence for increased chromatin content; and (3) the presence of multipolar or otherwise recognizably polyploid mitotic figures. All of these features must be identified for the diagnosis of anaplasia, although occasionally, when only a small biopsy is available, the presence of a single multipolar mitotic figure or an unequivocally gigantic tumor cell nucleus will suffice to establish the diagnosis. The frequency of anaplasia is approximately 8% and correlates with patient age. It is rare in the first 2 years of life (2%), and then increases to a relatively stable rate of about 13% in patients older than 5 years. It is significantly more frequent in African-American than in Caucasian patients and more frequent in girls than boys.³⁵

Anaplasia is subcategorized into diffuse and focal subtypes, based on the distribution of anaplastic changes within the tumor. The diagnosis of focal anaplasia requires that cells with anaplastic nuclear changes be confined to sharply circumscribed regions within the primary tumor, and that these cells are not present in any site outside the kidney parenchyma. The diagnostic criteria for diffuse anaplasia include any one of the following: (1) presence of anaplasia in any extrarenal site, including vessels of the renal sinus, extracapsular infiltrates, or nodal or distant metastases; (2) presence of anaplasia in a random biopsy specimen; (3) unequivocal anaplasia in one region of the tumor, coupled with extreme nuclear pleomorphism approaching the criteria of anaplasia (extreme nuclear unrest) elsewhere in the lesion; (4) presence of anaplasia in more than one tumor slide, unless (a) it is known that every slide showing anaplasia came from the same region of the tumor; or (b) anaplastic foci on the various slides are minute and surrounded on all sides by nonanaplastic tumor. The distinction between focal and diffuse anaplasia has been demonstrated to be prognostically significant.

Figure 29.2 Anaplastic WT with a large, darkly stained multipolar mitotic figure, near the center, and a markedly enlarged interphase nucleus to its left. Nuclei throughout this field exhibit increased variation in size and shape (H & E 600×).

Nephrogenic Rests

The existence of precursor lesions to WT has been recognized for many years. These nephrogenic rests are found in almost 1% of unselected pediatric autopsies, in 35% of kidneys with unilateral WT, and in nearly 100% of kidneys with bilateral WT. They are composed of abnormally persistent embryonal nephroblastic tissue with small clusters of blastemal cells, tubules, or stromal cells. Nephrogenic rests are classified by their position within the kidney. Intralobar nephrogenic rests (ILNR) are randomly distributed, but tend to be situated deep within the renal lobe, likely reflecting an earlier developmental insult to the kidney. These lesions are commonly stroma-rich and intermingle with the adjacent renal parenchyma. Perilobar nephrogenic rests (PLNR) are located at the periphery, are usually subcortical, sharply demarcated, and contain predominantly blastema and tubules. These presumably reflect later developmental disturbances in nephrogenesis. The type of nephrogenic rests observed in a particular WT relates to the underlying genetic and epigenetic changes. The term nephroblastomatosis is used to refer to the presence of multiple nephrogenic rests. Diffuse overgrowth of PLNR may produce a thick “rind” of blastemal or tubular cells that enlarge the kidney but preserve its original shape (Fig. 29.3). Only a small number of nephrogenic rests develop a clonal transformation into WT. When this happens, the WT is typically spherical and develops a pseudocapsule separating it from the nephrogenic rest. Some rests may become hyperplastic, with dramatic enlargement that preserves the shape of the preceding rest. Such lesions may be histologically indistinguishable from WT on biopsy unless the interface between the rest and the adjacent normal kidney is present within the sample. Hyperplastic nephrogenic rests may completely regress or differentiate following the administration of chemotherapy. The majority of nephrogenic rests become dormant or involute spontaneously. The presence of nephrogenic rests within a kidney resected for a WT indicates the need for monitoring the contralateral kidney for tumor development, particularly in young infants.

CLINICAL PRESENTATION AND DIAGNOSTIC WORKUP

The majority of children with WT present with an asymptomatic abdominal mass that is incidentally noted while bathing or dressing the child. Pain is seen in approximately 40% of patients, although this symptom is not well correlated with tumor rupture.³⁶ Fever is less commonly observed. Gross (18%) or microscopic (24%) hematuria may occur on an intermittent basis in children with WT.³⁶ Hypertension occurs in over a quarter of patients and is caused by increased renin secretion. The physical examination will demonstrate a mass that is typically smooth and eccentrically located in the abdomen toward the flank. The tumor may be fragile, and thus gentle and limited numbers of palpations should be undertaken. Features related to the WT mass and its effects on normal structures may include pulmonary insufficiency secondary to lung metastases, congestive heart failure, prominent abdominal wall vessels, varicocele related to obstruction of the IVC and consequent spermatic vein thrombosis, and rarely pulmonary embolus.

Figure 29.3 Perilobar nephrogenic rests. Grossly these PLNR are roughly wedge shaped following the contours of the renal lobule. The nephrogenic rest tissue is homogeneous and paler than the normal surrounding renal parenchyma.

Up to 10% of children with WT have a known syndromic association such as Denys-Drash, WAGR, or Beckwith-Wiedemann syndromes. Careful assessment for clinical features of aniridia, urogenital anomalies (hypospadias, cryptorchidism, pseudohermaphrodism), developmental delay, overgrowth, and hemihypertrophy should be carried out. A French study demonstrated an excess of congenital heart defects in patients with WT, as did a study in Great Britain at 1.8% of the study participants.³⁷^,³⁸

Approximately 5% to 7% of patients with WT have bilateral disease.² The majority will present with synchronous disease at diagnosis, and 1.2% of children will develop metachronous involvement of the contralateral kidney, usually within 4 years of the diagnosis of the original tumor.³⁹ This metachronous occurrence is more common in infants less than 12 months of age with PLNR in the nephrectomy specimen.

Patterns of Spread

WT may spread locally or hematogenously. Locally, the tumor may extend directly through the renal capsule and most typically develops an inflammatory pseudocapsule during its growth. The tumor may grow directly into the renal sinus or ureter. WT may also grow by contiguous spread through the renal vein into the IVC (4% to 10%), with rare direct extension into the right atrium.⁴⁰ WT spreads to regional lymph nodes in approximately 15% to 20% of cases. Hematogenous metastases in WT are uncommon at baseline diagnosis (12%), and when present most frequently involve the lung (80%), liver (15%), and, rarely, bone, bone marrow, or brain. MRT and CCSK have a greater propensity for bone and brain metastases. Baseline and follow-up imaging should examine these potential sites of spread.³⁶^,⁴¹

Differential Diagnosis

The clinical approach to a child with a renal mass begins with the assumption that the most likely diagnosis is WT. However, other benign and malignant intrarenal masses may mimic clinical and radiological features of WT. Leukemia, Burkitt lymphoma, rhabdomyosarcoma, sarcoma, and non-Wilms primary renal tumors may be mistaken on diagnostic imaging for WT. Benign conditions that may mimic WT include polycystic kidney disease, abscess, and hydronephrosis. Error rates in predicting a diagnosis of WT based on imaging studies have dropped from 7% to 10% in early SIOP and NWTSG trials to the current range of 2% to 5%.⁴²^,⁴³ As a cause of renal tumor, CMN predominates in the first month of life (54%), but its relative contribution diminishes rapidly to <10% by approximately 3 months of age.⁴⁴ Conversely, RCC should be considered in the adolescent. The primary extrarenal tumor that may be mistaken for WT is neuroblastoma, but the latter can usually be distinguished on diagnostic imaging by the absence of a claw sign (Fig. 29.4), adrenal or paraverterbral sympathetic ganglion origin, and a propensity for invasion rather than capsule formation.

Laboratory Workup

Laboratory evaluations that should be performed preoperatively include a complete blood count with differential, liver function tests, renal function including urinalysis, electrolytes, and serum calcium. Acquired von Willebrand disease can occur in approximately 1% to 2% of patients with WT. As a result, some clinicians recommend preoperative measurement of coagulation parameters (PT, PTT, von Willebrand factor antigen and activity levels, and factor VIII levels).⁴⁵

Imaging Studies

Initial imaging studies for suspected WT should confirm that the mass arises from the kidney, ascertain whether there is contiguous spread outside of the kidney including the IVC, determine whether the urinary tract anatomy is normal (looking for single, horseshoe, or ectopic kidneys), provide evidence as to the involvement of the opposite kidney, and assess whether there is metastatic involvement, most typically in the lung or liver.

Abdominal Imaging

Ultrasound is commonly used in the initial evaluation of a renal mass because it is rapidly available and usually requires no sedation. Color Doppler ultrasound has high predictive value in identifying whether there is intravascular tumor thrombus. Ultrasound, however, is operator dependent, limited by intra-abdominal gas and obesity, and not easily amenable to central review.⁴⁶ Once the diagnosis of a renal mass is established, a contrast-enhanced computed tomography (CT) scan is performed to further define the anatomy of the tumor. CT is highly sensitive (96%) in ruling out cavoatrial thrombus, leading to the conclusion that routine Doppler US is not required if a high-quality CT scan has already been performed.⁴⁷ CT has moderate specificity but relatively low sensitivity in the detection of preoperative WT rupture, with ascites beyond the cul-de-sac being the most predictive sign of rupture.⁴⁸ It is also very sensitive in identifying tumor or nephrogenic rests in the contralateral kidney. Magnetic resonance imaging (MRI) has replaced CT scans at some centers as a primary means of baseline abdominal imaging.⁴⁹ MRI has the advantage of decreasing exposure to ionizing radiation, though it is not adequate for assessment of the lungs and has the disadvantage of usually requiring general anesthesia. An emerging concern is the occurrence of gadolinium-related nephrogenic systemic fibrosis; individuals with a calculated GFR of less than 60 mL/min/1.73 m² appear to be most at risk for this devastating complication.⁴⁹^,⁵⁰

Figure 29.4 Axial CT scan of the abdomen demonstrating bilateral WTs. The larger right kidney tumor demonstrates the “claw” sign, in which the renal parenchyma is stretched around and cupping the tumor suggesting the organ of origin.

Lung Imaging

CT scanning provides the most sensitive method of detecting metastatic lung nodules, though there is significant interobserver variability in interpreting chest CT scans. A significant portion of small lung nodules represent nonmalignant conditions such as fibrosis, atelectasis, or infection, and this may be quite prominent in areas with endemic histoplasmosis.⁵¹ Nevertheless, recent evidence suggests that patients with small lung nodules detected on CT scan but not chest x-ray have a higher relapse rate if treatment is administered according to local primary tumor stage only.⁵²^,⁵³

Studies with limited numbers of patients have suggested that positron emission tomography does not appear to routinely add to conventional imaging techniques for the initial diagnostic workup of WT.⁵⁴^,⁵⁵ However, it may provide additional information with respect to residual disease at the end of therapy and extent of disease at relapse.⁵⁴

PROGNOSTIC FACTORS

The prognosis of children with WT is influenced by several factors including histology, stage, age at diagnosis, rapidity of response to therapy, and, increasingly, molecular markers.

Histology

Histology remains the most powerful prognostic factor for pediatric renal tumors. The COG classification system divides WTs into two broad histologic types: favorable and anaplastic histology (see pathology section for descriptions and definitions). The anaplastic histology tumors are further divided into diffuse and focal, based on the distribution of anaplastic cells throughout the tumor. Favorable-histology tumors have the best outcomes, diffuse anaplastic tumors have the worst outcomes, and focal anaplastic tumors have intermediate prognosis.³⁵ The SIOP histologic classification schema is more complex than the COG schema because it takes into account the histologic response to chemotherapy (Table 29.3). In the SIOP classification system, completely necrotic tumors have an outstanding prognosis and blastemal-predominant tumors have a high risk of recurrence.⁵⁶^,⁵⁷ The adverse prognostic significance of blastemal cells is greater in WTs exposed to chemotherapy compared with untreated tumors.

Stage

Stage continues to carry important prognostic significance for WT. There are two main staging systems in use for WT. The COG
classification is based on immediate nephrectomy and takes into account surgical-pathological findings with imaging for distant metastasis (Table 29.4). SIOP utilizes a preoperative chemotherapy approach, and staging criteria are based on a combination of prechemotherapeutic imaging to define metastatic disease and local operative findings following chemotherapy. Although the stage definitions are similar, the prechemotherapy stage does not have equivalent clinical significance to the postchemotherapy stage, thus confounding head-to-head comparisons of SIOP and NWTSG/COG trial results.

Age

Age has long been known to correlate with prognosis in WT, with older age associated with adverse prognosis. There are several factors that explain this association. First, there is a subset of very young patients whose WTs have favorable biology and have outstanding outcomes with no or minimal chemotherapy. Evidence from the NWTSG suggested that children less than 2 years of age, small tumor size, and stage I WT have excellent survival when managed with nephrectomy alone.⁵⁸^,⁵⁹ A similar subgroup was identified in the United Kingdom WT study. In this study, patients less than 4 years old with stage I WT had outstanding outcomes (94% event-free survival [EFS]) when treated with 10 weeks of vincristine monotherapy.⁶⁰ A second factor explaining the age effect is that anaplasia is distinctly uncommon in patients less than 2 years old and becomes more common in the older age groups.⁶¹ Finally, adults with WT seem to fare worse than children. This effect has been ameliorated when adults are treated with modernday pediatric treatment protocols, but it still seems that adults fare worse than children, particularly those with higher-stage WT.⁶²^,⁶³^,⁶⁴ A difference between adults and children is that adults are more prone to vincristine-induced neuropathy than children and cannot tolerate the full complement of therapy.

TABLE 29.4 Children’s Oncology Group Staging system for WT

Stage I	Tumor limited to kidney, completely resected. The renal capsule is intact. The tumor was not ruptured or biopsied prior to removal. The vessels of the renal sinus are not involved. There is no evidence of tumor at or beyond the margins of resection. NOTE: For a tumor to qualify for certain therapeutic protocols as Stage I, regional lymph nodes must be examined microscopically
Stage II	The tumor is completely resected, and there is no evidence of tumor at or beyond the margins of resection. The tumor extends beyond the kidney, as is evidenced by any one of the following criteria: There is regional extension of the tumor (i.e., penetration of the renal capsule, or extensive invasion of the soft tissue of the renal sinus, as discussed below) Blood vessels within the nephrectomy specimen outside the renal parenchyma, including those of the renal sinus, contain tumor. Note: Rupture of spillage confined to the flank, including biopsy of the tumor, is no longer included in Stage II and is now included in Stage III
Stage III	Residual nonhematogenous tumor present following surgery, and confined to abdomen. Any one of the following may occur: Lymph nodes within the abdomen or pelvis are involved by tumor. (Lymph node involvement in the thorax, or other extraabdominal sites is a criterion for stage IV) The tumor has penetrated through the peritoneal surface Tumor implants are found on the peritoneal surface Gross or microscopic tumor remains postoperatively (e.g., tumor cells are found at the margin of surgical resection on microscopic examination) The tumor is not completely resectable because of local infiltration into vital structures Tumor spillage occurring either before or during surgery The tumor is treated with preoperative chemotherapy (with or without a biopsy regardless of type- tru-cut, open or fineneedle aspiration) before removal Tumor is removed in greater than one piece (e.g., tumor cells are found in a separately excised adrenal gland; a tumor thrombus within the renal vein is removed separately from the nephrectomy specimen) Extension of the primary tumor within vena cava into thoracic vena cava and heart is considered Stage III, rather than Stage IV, even though outside the abdomen
Stage IV	Hematogenous metastases (lung, liver, bone, brain, etc.), or lymph node metastases outside the abdominopelvic region are present. (The presence of tumor within the adrenal gland is not interpreted as metastasis, and staging depends on all other staging parameters present)
Stage V	Bilateral renal involvement by tumor is present at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of the extent of disease

Molecular Markers

LOH for polymorphic DNA markers on chromosomes 1p and 16q has been shown to be associated with inferior relapse-free (RFS) and overall survival (OS) in patients with favorable-histology WT. The greatest effect is in tumors with LOH at both 1p and 16q.⁶⁵ The recently completed COG trials assessed whether increasing therapy for patients with LOH at 1p and 16q improved outcomes; results have not yet been reported. Gain of chromosome 1q, as measured by comparative genomic hybridization, has also been correlated with adverse outcome.⁶⁶^,⁶⁷ This association was recently confirmed in an analysis of 212 patients treated on NWTS-4.⁶⁸ In this study, 8-year EFS was 76% (95% CI, 63% to 85%) for patients with 1q gain and 93% (95% CI, 87% to 96%) for those lacking 1q gain (p = 0.0024). Eight-year OS was 89% (95% CI, 78% to 95%) for those with 1q gain and 98% (95% CI, 94% to 99%) for those lacking 1q gain (p = 0.0075). Interestingly, gain of 1q correlates closely with LOH at 1p and 16q, so it is possible that 1q gain is the more biologically relevant lesion.

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