Wilms Tumor

Wilms tumor, also termed nephroblastoma, is the most common malignancy of the pediatric urinary tract, occurring in 7 to 10 per million children younger than 15 years. There are approximately 500 new cases of Wilms tumor annually in the United States.¹ Wilms tumor accounts for approximately 6% of all pediatric malignancies and at least 85% of solid renal masses.^2,3 It typically affects children under the age of 6, but is uncommon in young infants; the median age at presentation is 3.5 years. This tumor is rare in individuals over the age of 10 years.^4,5 Worldwide, Wilms tumor occurs without a gender predilection. In the United States, however, the frequency is slightly higher among girls than among boys. The frequency of Wilms tumor is lower in Asians than in whites.⁴

Treatment of unilateral Wilms tumor consists of nephrectomy and multimodality chemotherapy, with or without radiation therapy. In the United States, the standard treatment technique is nephrectomy at the time of diagnosis for all resectable lesions, followed by chemotherapy. Radiotherapy is useful for metastasis or residual disease, such as tumor spillage at the time of surgery or when there are known peritoneal tumor implants. Removal of metastatic lung nodules is sometimes indicated. In Europe, most patients receive several weeks of chemotherapy prior to nephrectomy, sometimes with percutaneous biopsy of the tumor at the time of diagnosis. The outcomes of these approaches are similar. Approximately 5% of patients with Wilms tumor have synchronous bilateral disease. The treatment approach to these children usually consists of an initial biopsy, subsequent chemotherapy, and delayed surgery. Surgery is tailored to preserve as much functional renal tissue as possible. The survival rate for these patients is similar to that of unilateral Wilms tumor.^6–8

Age at diagnosis, gender, tumor histology, and stage are important prognostic factors for patients with Wilms tumor. A younger age at diagnosis is associated with a greater likelihood of long-term survival. Unfavorable histology of Wilms tumor is more common in girls than in boys. The overall 5-year survival rate for Wilms tumor is approximately 90%.⁹ Stage 1 favorable histology is associated with a greater than 90% survival rate, regardless of tumor size.¹⁰ Children treated for Wilms tumor are at increased risk for second malignant neoplasms, with a cumulative incidence of 1.6%, representing more than 8 times the expected incidence.¹¹ The risk of developing leukemia or lymphoma is greatest in the first 8 years after treatment; the risk of developing a solid tumor does not appear to diminish with time. Potential late effects of therapy include cardiotoxicity, renal dysfunction, and reproductive problems.⁸

Wilms tumor is a genetically heterogeneous neoplasm that occurs as both a sporadic and a familial lesion. The sporadic form constitutes approximately 95% of Wilms tumor cases. Approximately 1% of children with Wilms tumor have a known familial predisposition to the lesion, typically expressed as an autosomal dominant trait. The kidneys of those patients with the familial forms of Wilms tumor usually harbor nephrogenic rests. The hereditary form of Wilms tumor tends to occur at an earlier age than the sporadic form, and tends to be bilateral or multicentric. Nearly all bilateral Wilms tumors are the hereditary type.^12,13

Wilms tumor is an embryonic renal tumor that apparently results from aberrant mesenchymal stem cell differentiation caused by the loss of a tumor suppressor gene(s). There are at least 2 chromosomal loci on 11p associated with Wilms tumor: 11p13 (WT1) and 11p15 (WT2). The Wilms tumor predisposition gene, WT1, contains 10 exons and encodes a transcription factor. The target genes regulated by WT1 include genes that code for transcription factors and for growth factors and their receptors. Experimental disruption of WT1 in mice results in absence of the kidneys and gonads. In particular, WT1 appears to be crucial for the appropriate differentiation of renal epithelium during nephrogenesis. A third locus (WT3) is suggested by familial instances of Wilms tumor that are not linked to WT1 or WT2; current evidence suggests 19q and 17q locations. There is evidence of multiple other chromosomal sites that may also harbor Wilms tumor predisposition genes (e.g., 16q, 1p, and 7p). Loci on chromosomes 16q and 1p have been implicated in the progression of Wilms tumor and may serve as molecular prognostic markers.^14–17

Wilms tumor can occur in association with a variety of syndromes and isolated congenital anomalies. Approximately 5% of patients with Wilms tumor have 1 or more genitourinary anomalies such as renal fusion anomalies, renal hypoplasia, ectopic kidney, cryptorchidism, and hypospadias.¹⁸ Therefore, careful inspection of images for the presence of an anomaly is an important component of the diagnostic imaging evaluation. There is an increased risk for Wilms tumor in patients with a horseshoe kidney; horseshoe kidney is nearly twice as common in patients with Wilms tumor as in the general population.¹⁹ A preoperative diagnosis of this complicating anomaly is useful to the surgeon. However, the large size of most Wilms tumors results in considerable displacement and distortion of the renal parenchyma, which can obscure the isthmus of a horseshoe kidney on imaging studies.²⁰

Syndromes that are associated with Wilms tumor include WARG syndrome, hemihypertrophy, Beckwith-Wiedemann syndrome (BWS), Denys-Drash syndrome, neurofibromatosis type 1, Sotos syndrome, and Perlman syndrome.⁵ The combination of bilateral nephroblastomatosis, aniridia, and 11p13 deletion results in the development of Wilms tumor in nearly all affected individuals. The risk for Wilms tumor is 40% in patients with aniridia, 5% to 10% in patients with BWS, and 5% (by the age of 6 years) in children with idiopathic hemihypertrophy. The association of aniridia with Wilms tumor is exclusively with the sporadic form of aniridia, rather than the more common familial form. There is an increased frequency of bilateral Wilms tumors in children with aniridia, and the presentation tends to occur at a younger age than in the general population (Figure 49-1). WARG syndrome refers to the combination of Wilms tumor, aniridia, genital abnormalities, and mental retardation.

Approximately 3% of Wilms tumor patients have some form of hemihypertrophy. Hemihypertrophy refers to morphological asymmetry in body development. The spectrum of severity ranges from enlargement of a single digit to hypertrophy of an entire half of the body. Children with hemihypertrophy are also at increased risk for the development of other renal and adrenal tumors, such as nephroblastomatosis, adrenal cortical tumors, and adrenal hyperplasia. Renal anomalies that occur with an increased frequency in patients with hemihypertrophy include benign nephromegaly (unilateral or bilateral), medullary sponge kidney, ectopic kidney, and renal cysts.

Clinical Presentation

Most Wilms tumors are quite large at the time of diagnosis. This is in part due to the usual lack of substantial systemic symptoms; children with this neoplasm typically are clinically well and thriving despite the presence of the rapidly growing renal tumor. The most common presenting complaint is abdominal fullness or a palpable upper abdominal/flank mass. This clinical pattern is somewhat different from neuroblastoma, which is the major differential consideration. Most children with neuroblastoma have systemic manifestations of the disease at the time of presentation, such as failure to thrive, bone pain, and anemia. Weight loss, malaise, and anemia can occur with Wilms tumor, but are uncommon.

In addition to an abdominal mass, potential signs and symptoms of Wilms tumor include abdominal pain (35%), hematuria (25%), fever (20%), and hypertension (25%). Microscopic hematuria in these patients can occur with or without a history of trauma. However, this large neoplasm is susceptible to hemorrhage with abdominal trauma, even when the injury seems trivial. Hematuria in any child with a history of minor trauma should raise the suspicion of a renal tumor or congenital urinary tract lesion (e.g., hydronephrosis) and prompt an appropriate workup.

Hypertension is common in patients with Wilms tumor.²¹ Hypertension in these patients is most often due to parenchymal ischemia (elevated renin production) related to compression of renal vessels by the mass. Occasionally, there is autonomous renin secretion by the neoplasm. Hypertension resolves in essentially all Wilms tumor patients after nephrectomy. There are also rare instances in which children with Wilms tumor present with symptoms suggesting the production of another bioactive substance by the tumor; elevated erythropoietin secretion can lead to polycythemia.²²

Physical examination of the child with Wilms tumor typically demonstrates a fixed flank mass that has a smooth, firm consistency. The lesion sometimes bulges across the midline. An uncommon sign of Wilms tumor is a varicocele, due to obstruction of the spermatic vein; this most often occurs with a left-sided lesion.

Pathology

Wilms tumor is an embryonic neoplasm that arises from primitive metanephric blastema. This neoplasm has considerable histological diversity. The lesion is predominantly composed of various renal tissues, including blastema, stroma, and epithelium. In addition, some lesions contain skeletal muscle, cartilage, and squamous epithelium. Areas of hemorrhage, necrosis, and cyst formation are common. Occasionally, a Wilms tumor is predominantly cystic, resembling a multilocular cystic nephroma. A lesion that contains tissues differentiated along lines not normally found in the kidney is termed a teratoid Wilms tumor. This rare variant contains predominantly heterologous tissues, such as adipose tissue, glial tissue, muscle, cartilage, or bone. The histological characteristic of anaplastic Wilms tumor is the presence of atypical mitoses or hyperchromatic cells that contain large nuclei. Approximately 95% of patients with Wilms tumor have a lesion with favorable histology that is associated with a good prognosis.

The gross appearance of a typical Wilms tumor is a large predominantly solid mass that causes distortion of the collecting system and remaining renal parenchyma. A pseudocapsule is present at the margin of the mass. The lesion can be unilateral and unicentric (88%), unilateral multicentric (7%), or bilateral (5%) (Figure 49-2). Wilms tumor can break through the renal capsule to invade the perirenal fat and adjacent structures. Extension into the renal vein can progress to involvement of the inferior vena cava and right atrium. Other potential sites of local extension include the renal sinus and intrarenal or perirenal lymphatics. Distant metastatic disease is identified during the initial evaluation of 12% of children with Wilms tumor. The most common sites are the lungs (10% of patients at diagnosis), regional lymph nodes, and the liver (2%). Synchronous bilateral nephroblastoma occurs in approximately 5% of children with Wilms tumor.²³

Imaging

Because most Wilms tumors are quite large at the time of clinical presentation, soft tissue fullness in the flank is usually visible on abdominal radiographs. In some patients, there is displacement of gas-filled bowel from the ipsilateral hemiabdomen. Only rarely is calcification visible in the mass. Lung nodules may be present in those patients with metastatic disease.

Wilms tumor typically has a heterogeneous character on sonography, due to the varied tissue composition and the presence of hemorrhage and necrosis. Necrosis and hemorrhage tend to be less pronounced in smaller Wilms tumors than in larger lesions (Figure 49-3). When present, calcifications may produce foci of acoustic shadowing. Sonography demonstrates intravenous extension of tumor as echogenic material within an enlarged renal vein or the inferior vena cava. Color Doppler examination is helpful to visualize flow around the tumor thrombus and thereby determine the severity of obstruction. The demonstration of arterial flow in small vessels within the tumor thrombus confirms the neoplastic nature of the intraluminal material, and provides definitive distinction from bland thrombus.^24,25

CT evaluation most often shows a Wilms tumor as a solid intrarenal mass that displaces and distorts the remaining normal parenchyma and the collecting system. The lesion usually has attenuation values that are equal to or lower than those of normal parenchyma on unenhanced images. Calcifications are visible in approximately 10% of these lesions. With the rare teratoid variant, areas of fat attenuation may be present as well as calcifications.²⁶ Wilms tumor typically has an irregular enhancement pattern. Compression of renal parenchyma peripherally may result in a rim of prominent enhancement (Figure 49-4). Central areas of necrosis or cyst formation do not enhance.^25,27

The renal origin of a large Wilms tumor is sometimes difficult to determine on CT. This is particularly problematic when the growth pattern is predominantly exophytic. Careful inspection of contrast-enhanced images nearly always demonstrates a rim of enhancing renal parenchyma draped around the tumor. The renal capsule usually confines the tumor; therefore, adjacent structures tend to be compressed or displaced rather than invaded. Even when quite large, Wilms tumor causes lateral displacement of the aorta and inferior vena cava rather than the pattern of encasement that is typical of neuroblastoma; neuroblastoma is an important consideration in the differential diagnosis.²⁸ Likewise, elevation of the aorta does not usually occur with Wilms tumor. Because the renal sinus is an area of relative weakness of the renal capsule and because the renal sinus area contains abundant lymphatic and vascular structures, this is the most frequently involved site of local spread of a Wilms tumor. CT may demonstrate retroperitoneal metastatic lymphadenopathy. Even with retroperitoneal lymphadenopathy, however, extensive vascular encasement is unusual with Wilms tumor. CT shows the predominantly cystic variant of Wilms tumor as a multiloculated cystic and solid mass.

Careful inspection of the contralateral kidney is essential for all Wilms tumor patients, due to the potential for nephrogenic rests and contralateral synchronous tumor. Liver metastases, when present, appear on contrast-enhanced CT as low-attenuation round or oval lesions. A large Wilms tumor can invade or compress the portal vein, resulting in portal hypertension; CT may demonstrate splenomegaly in this instance. Tumor thrombus appears as a filling defect in the renal vein or inferior vena cava (Figure 49-5). CT examination of the chest to search for lung metastasis is usually performed in all patients with a suspected diagnosis of Wilms tumor. Metastatic Wilms tumor to the lungs most often results in nodules that are peripheral or subpleural in location. In those patients with tumor rupture, CT may show hyperattenuating hemoperitoneum. A small amount of reactive intraperitoneal fluid, however, can occur without tumor rupture or intraperitoneal spread. Intraperitoneal metastasis appears as peritoneal, mesenteric, or omental solid masses.

With MR, coronal T1-weighted images are usually most useful for differentiating the renal origin of a Wilms tumor from an adrenal or hepatic lesion. There is distortion of the remaining renal parenchyma and collecting system. The mass has a heterogeneous character due to hemorrhage and necrosis. Wilms tumor is typically hypointense or isointense to normal renal parenchyma on T1-weighted images. Necrotic areas and cysts are hypointense, whereas areas of subacute hemorrhage produce relatively high signal intensity. On T2-weighted sequences, Wilms tumor is hyperintense relative to most adjacent soft tissue structures, but produces similar signal intensity as renal parenchyma. Foci of calcification within the tumor are hypointense on both T1- and T2-weighted images. Contrast-enhanced T1-weighted images are helpful for accurately defining the margins of the mass. The mass undergoes a lesser degree of enhancement than normal renal parenchyma with IV gadolinium.^25,29,30

MRI is equivalent to venography for the detection of venous tumor extension. The sensitivity for the detection of renal vein tumor thrombus is 70% to 90%, whereas thrombus in the inferior vena cava is detected with nearly 100% sensitivity. MR occasionally demonstrates infiltration of the wall of the vena cava as well. The examination should include careful assessment of the vena cava, the ipsilateral and contralateral renal veins, the hepatic veins, and the right atrium. Extension of tumor thrombus above the level of the hepatic vein confluence has important surgical implications, since these patients require temporary interruption of hepatic blood flow during surgery.

Mesoblastic Nephroma

Mesoblastic nephroma is a mesenchymal neoplasm of the infantile kidney. It is the most common renal neoplasm to present in the first 3 months of life and accounts for about half of solid renal masses in children younger than 6 months of age.³¹ Approximately 80% of mesoblastic nephromas are discovered during the first month of life. Mesoblastic nephroma rarely occurs more than 6 months after birth or during adulthood; many of these tumors likely arise in utero. Nearly all of these tumors are histologically benign. The prognosis is excellent with appropriate surgical treatment.^32,33

Although some of these lesions are asymptomatic until palpated in the neonate, a variety of clinical manifestations of mesoblastic nephroma can occur during pregnancy, most often identified during the third trimester. The typical in utero presentation is that of rapid increase in fundal height due to the acute onset of polyhydramnios. The mechanism by which the neoplasm causes polyhydramnios is unclear. Increased blood flow to the affected kidney, impaired concentrating ability of the kidney, polyuria due to hypercalcemia, and obstruction of the GI tract are possible factors. Fetal sonography or MR shows a solid renal mass. Doppler examination shows prominent blood flow to the lesion; hydrops is a rare complication of this tumor.^34–36

In the neonate, mesoblastic nephroma usually is of sufficient size to be readily apparent on physical examination. The flank mass is firm on palpation. Hematuria occurs in 10% to 20% of children with mesoblastic nephroma. Other potential findings include hypertension and hypercalcemia. Hypertension in these infants is due to elevated renin production by the affected kidney. Calcium and renin levels return to normal after tumor resection. Nephrectomy is curative for nearly all patients with mesoblastic nephroma. The risk of recurrence increases with the age of the infant at the time of tumor resection; recurrence is also more common when there is incomplete resection or intraoperative tumor rupture. The risk of recurrence increases with the age of the patient at the time of diagnosis.³³

Mesoblastic nephroma is a mesenchymal tumor that is composed of spindle-shaped cells that infiltrate the normal renal tissue; the tumor blends imperceptibly with normal parenchyma. These tend to be large tumors that involve at least half of the kidney. Although not encapsulated, the tumor is usually well circumscribed; however, extension beyond the renal capsule can occur. On pathological examination, there is a dense stromal architecture of the tumor. In contradistinction to most other renal malignancies, hemorrhage, necrosis, and cyst formation are uncommon in mesoblastic nephroma. Most of these lesions are composed of sheets of bands of immature connective tissue cells, which contain scattered islands of immature dysplastic renal tubules and glomeruli. Smooth muscle and cartilage are commonly present.

There are 2 histological forms of mesoblastic nephroma; each has distinct biological behavior. The fibromatous type described above is most common; this is histologically and biologically benign and usually is diagnosed early in infancy. The atypical, or cellular, type is potentially malignant, and tends to occur in older children. This later form of mesoblastic nephroma contains a very large number of mitotic cells. Distant metastasis can occur with this variant; local recurrence after nephrectomy is more common than with the fibromatous type.³⁷

Mesoblastic nephroma is usually quite large at the time of diagnosis; abdominal radiographs show a large soft tissue density flank mass (Figure 49-6). Rarely, calcifications are present. The mass may be large enough to cross the midline and displace gas-filled loops of bowel from the ipsilateral hemiabdomen. Because this tumor is usually detected in young infants, the initial cross-sectional imaging technique for most patients is sonography. In keeping with the pathological characteristics of this lesion, sonography typically shows a solid mass with low-level internal echoes. In some patients, a central hypoechoic zone is surrounded by a thin echogenic rim that is in turn surrounded by a band of hypoechoic tissue.³⁸

On CT examination, mesoblastic nephroma is demonstrated as a large intrarenal mass, often at least partially surrounded by functioning renal parenchyma. The margins are usually well defined. Images should be inspected for evidence of penetration of the renal capsule and extension into the perinephric space or deeper into the retroperitoneum. The mass produces lower attenuation values than renal parenchyma on contrast-enhanced images. Trapped functional glomeruli and tubules within the tumor sometimes are sufficient for the visualization of minimal contrast excretion on delayed images. Functional tissue within a mesoblastic nephroma may also be of sufficient quantity to produce some uptake on renal scintigraphy utilizing cortical agents such as dimercaptosuccinic acid (DMSA), although the mass is markedly photopenic in comparison to the adjacent renal parenchyma.³⁹

Mesoblastic nephroma may have a somewhat heterogeneous character on MRI. As with other cross-sectional studies, the margins are well defined, although capsular penetration occasionally occurs. The mass is moderately hypointense to normal renal parenchyma on T1-weighted images and hyperintense on T2-weighted images. The contrast enhancement pattern is usually somewhat heterogeneous, as with CT.

Clear Cell Sarcoma

Clear cell sarcoma, or bone metastasizing renal tumor of childhood, accounts for approximately 3% of pediatric renal neoplasms reported to the National Wilms Tumor Study. This lesion has a propensity for metastatic spread to the skeletal system and brain. The peak incidence of clear cell sarcoma is between 3 and 5 years of age, similar to that of Wilms tumor. There is a striking male predominance. The clinical presentation is nonspecific, usually as a palpable abdominal mass.^40–42

Clear cell sarcoma was formerly considered a variant of Wilms tumor, but is now recognized as a distinct pathological entity. This is a more aggressive neoplasm than Wilms tumor. The relapse rate of clear cell sarcoma is at least 60%. The long-term survival rate is only 50% to 60%. Between 50% and 75% of patients with clear cell sarcoma develop bone metastasis. In contradistinction to Wilms tumor, lung metastasis is uncommon with this lesion. Rare instances of brain and liver metastasis have been reported. Treatment of clear cell sarcoma consists of nephrectomy and chemotherapy.⁴³

The most characteristic diagnostic imaging pattern of clear cell sarcoma of the kidney is a combination of a large renal mass and multiple lytic bone lesions. Intravascular extension is much less frequent than with Wilms tumor. The mass is predominantly solid, with intermixed areas of necrosis or hemorrhage. Cross-sectional imaging studies commonly show cystic areas within the mass; these may range in diameter from a few millimeters to a few centimeters. Despite these features, diagnostic imaging does not allow reliable preoperative differentiation from other renal malignancies.⁴⁴

Metastatic bone lesions due to clear cell sarcoma of the kidney are osteolytic and most often located in the flat bones, femurs, and humeri. Tubular bone metastases in these patients tend to be located in a proximal aspect of the involved bone. Metastatic lesions may produce abnormal increased radiopharmaceutical uptake with bone scintigraphy; however, many of the metastatic foci are associated with little bone turnover and are not visible with scintigraphy. Therefore, detection and characterization of metastatic disease in children with clear cell sarcoma are usually accomplished with the combination of skeletal scintigraphy and a radiographic skeletal survey.

Rhabdoid Tumor

Rhabdoid tumor (fetal rhabdomatous nephroblastoma) is a highly malignant neoplasm of the kidney that occurs exclusively in children. This lesion accounts for approximately 2% of renal tumors registered with the National Wilms Tumor Study.^45,46 Rhabdoid tumor of the kidney is most often diagnosed in infants and very young children; the median age is 11 to 13 months. This neoplasm is extremely rare in individuals over the age of 5 years. This tumor is slightly more common in boys; the male:female ratio is 1.5:1.

In comparison to Wilms tumor, rhabdoid tumor of the kidney affects younger patients, more commonly metastasizes to the brain, and has a poorer prognosis. Occasional patients with rhabdoid tumor of the kidney have hypercalcemia, apparently due to tumor secretion of parathormone. An important characteristic of rhabdoid tumor is the association with synchronous or metachronous primary intracranial neoplasms. The most common brain lesions in these patients are in the posterior fossa and near the midline, for example, medulloblastoma, ependymoma, and primitive neuroectodermal tumor.⁴⁷

Recent studies suggest that there is a common genetic basis for rhabdoid tumors that arise in the kidneys, central nervous system (CNS), and other extrarenal sites.⁴⁸ A deletion or mutation in the tumor suppressor gene INI1 on chromosome 22 predisposes to the development of these tumors. Rhabdoid tumor of the kidney has a high relapse rate and carries the worst prognosis of all pediatric renal neoplasms. The mortality associated with this tumor is greater than 80%. The survival rate is greater for female patients. Nearly all children with metastatic rhabdoid tumor die of the disease.⁴⁹

Rhabdoid tumor of the kidney derives its name from the presence of large cells that are histologically reminiscent of rhabdomyoblasts. However, there are no muscle elements in this lesion and it is not related to rhabdomyosarcoma. Rhabdoid tumor likely arrises from primitive cells that are involved in the formation of the renal medulla. Pathological examination typically shows involvement of perihilar renal parenchyma. There is a wide histological spectrum, described as classical, epithelioid, sclerosing, lymphomatoid, histiocytoid, vascular, pseudopapillary, and cystic.⁴⁶

Cross-sectional imaging studies show a rhabdoid tumor of the kidney as a large soft tissue mass, usually arising from the central portion of the kidney and compressing the surrounding parenchyma. In some patients, there is irregular thickening of the renal capsule. Subcapsular nodules or fluid may be present. Linear calcifications may outline tumor lobules. A common CT finding with this tumor is a prominent eccentric nonenhancing crescent that is due to subcapsular hemorrhage or peripheral tumor necrosis adjacent to tumor lobules. Vascular invasion and local extension are common. The most common sites of metastasis are lungs, liver, brain, and skeleton (Figure 49-7).^{27,47,50–52}

Renal Cell Carcinoma

Although renal cell carcinoma is rare in young children, the incidence is approximately equal to that of Wilms tumor during the second decade of life. This neoplasm accounts for less than 7% of primary renal tumors in patients up to the age of 20 years. Only 5% of renal cell carcinomas occur in children; these patients generally present after the age of 5 years. There is no substantial gender prediction. Patients with von Hippel-Lindau syndrome and tuberous sclerosis are at increased risk for renal cell carcinoma (sometimes multicentric or bilateral), although this complication does not usually occur during childhood. Long-term survival of children with renal cell carcinoma is approximately 50% to 65%. Age at diagnosis is a prognostic factor, with improved survival of children younger than 10 years. Renal cell carcinoma is poorly responsive to chemotherapy.^53–56

The potential presenting features of renal cell carcinoma include a palpable abdominal mass, flank pain, and hematuria. This neoplasm can cause hypertension. Flank pain or hematuria following minor abdominal trauma is a relatively common initial presentation of renal cell carcinoma in children. In comparison to Wilms tumor, renal cell carcinoma tends to be smaller at the time of presentation and is more frequently associated with hematuria.⁵⁷

Renal cell carcinoma is an adenocarcinoma that has some degree of renal tubular differentiation. Nonpapillary histology is much more common than the papillary type. Grossly, there is an infiltrative solid mass, with variable necrosis, hemorrhage, calcification, and cystic degeneration. The normal parenchyma is distorted. There is a pseudocapsule. Most renal cell carcinomas have invaded locally at the time of resection, with spread to adjacent retroperitoneal lymph nodes. Approximately 20% of patients have distant metastatic disease at the time of presentation; the lungs, skeletal system, liver, and brain are the most common sites. In comparison to Wilms tumor, renal cell carcinoma is more often bilateral and more often metastasizes to bone. Many pediatric renal cell carcinomas have an XP11.2 translocation. Table 49–1 summarizes the most commonly utilized staging system for renal cell carcinoma.⁵⁸

The imaging features of renal cell carcinoma in children are nonspecific. Standard abdominal radiographs sometimes show flank fullness or a mass. In many children, however, the mass is too small to produce visible radiographic alterations. Calcifications are sometimes present. The calcifications within a renal cell carcinoma tend to be denser, more central, and more homogeneous than those in Wilms tumor.⁵⁹

Sonography can be utilized to confirm the renal origin of the mass. The remaining normal renal parenchyma is displaced and distorted. As with Wilms tumor, imaging in various planes is helpful to document the renal origin of the lesion. Areas of necrosis are sometimes present, resulting in hypoechoic regions.

On unenhanced CT images, renal cell carcinoma usually has similar attenuation values as normal renal parenchyma; occasionally, the mass is slightly hyperattenuating. The attenuation of the mass is lower than that of parenchyma on contrast-enhanced CT images. The interface between the tumor and the adjacent parenchyma is usually somewhat ill defined. Necrosis and hemorrhage are often present, resulting in a heterogeneous character of the lesion. Calcification is demonstrable with CT in approximately 25% of renal cell carcinomas (Figure 49-8).

Renal cell carcinoma produces relatively low signal intensity on T1-weighted MR images and is hyperintense on T2-weighted images. It often has a hypointense rim on T2-weighted images; visualization of an intact pseudocapsule suggests a lack of perinephric fat invasion. The signal intensity of the bulk of the mass is sometimes similar to that of normal renal parenchyma on standard images; gadolinium-enhanced images are essential for accurate characterization of the tumor margins and for detecting the carcinoma itself when small. The mass undergoes much less enhancement than renal parenchyma. As with Wilms tumor, MR is quite helpful for detecting vascular invasion. The pattern of contrast enhancement helps to distinguish tumor thrombus from bland thrombus.⁶⁰

There is a substantial risk for recurrence of renal cell carcinoma despite technically satisfactory surgical resection of the primary lesion. Most recurrences occur within 2 years after surgery. Recurrence may occur at the original tumor site or, more frequently, at a remote site. In decreasing order of frequency, potential sites of recurrence for renal cell carcinoma include lung, bone, nephrectomy site, liver, lymph nodes, brain, and adrenal gland (uncommon). The early detection of lung metastasis is particularly important, as surgical removal of these lesions can result in a long disease-free period and improved survival.⁶¹

Radiography, CT, and scintigraphy serve important roles for followup of patients after resection of a renal cell carcinoma. The typical appearance of lung metastasis from renal cell carcinoma on standard radiographs or CT is 1 or more well-defined round or oval nodules. With scintigraphy, a metastatic bone lesion may appear as a photopenic focus surrounded by increased uptake, as a purely cold focus, or as a purely hot focus. The lesions are lytic on CT and radiographs. A bone recurrence is demonstrated with MR as a somewhat heterogeneous solid mass that produces intermediate signal intensity on both T1- and T2-weighted images; contrast enhancement is visible on both MR and CT. Recurrence at the nephrectomy site can be demonstrated with CT, MR, or sonography, typically as a solid mass with central necrosis. The CT or MR appearance of brain metastasis is that of enhancing nodules with surrounding edema. Liver metastases are hypoechoic on sonography and hypoattenuating on contrast-enhanced CT.⁶²

Nephrogenic Rests and Nephroblastomatosis

Incomplete induction of the metanephric blastema into mature renal parenchymal tissue by the ureteral bud can result in persistent embryonal renal tissue within the mature kidney. Isolated foci of this embryonal tissue are termed nephrogenic rests, whereas diffuse or bilateral involvement is termed nephroblastomatosis. Nephrogenic rests are further classified into intralobar and perilobar types. Perilobar nephrogenic rests tend to be well circumscribed and located peripherally in the cortex or in a column of Bertin. Intralobar rests can occur anywhere within the kidney. They usually have irregular morphology and can occur singly or in a small number. Table 49–2 summarizes the most common types of nephroblastomatosis. Persistent embryonal renal tissue may regress spontaneously (sclerotic nephrogenic rest), remain stable indefinitely, proliferate (hyperplastic nephrogenic rest), give rise to a benign neoplasm, or give rise to a Wilms tumor.^63,64

Persistent embryonal renal tissue is present in approximately 1% of all infants, and spontaneous regression occurs over the first few months of life in most individuals. Subsequent malignant degeneration of this tissue is an important, but uncommon, etiology of Wilms tumor. Various factors influence the risk of malignant degeneration in patients with persistent embryonal renal tissue. Malignant transformation is more common with the intralobar type than with the perilobar type of nephrogenic rest. Intralobar nephrogenic rests are associated with chromosomal abnormalities in the 11p13 locus (WT1), and are common in patients with sporadic aniridia (100%), WARG syndrome, and Drash syndrome (78%). About one-third of patients with sporadic aniridia go on to develop Wilms tumor. Perilobar rests are often associated with abnormalities in the 11p15 locus (WT2), and are common in children with Beckwith-Wiedemann syndrome (BWS), hemihypertrophy, Perlman syndrome (visceromegaly, gigantism, cryptorchidism, polyhydramnios, abnormal facies), and trisomy 18.⁶³

Nephroblastomatosis is a precursor of Wilms tumor, although the overall risk is small. The risk varies among the different types of nephroblastomatosis. When nephroblastomatosis is demonstrated pathologically in a kidney removed for Wilms tumor, the risk for the development of a Wilms tumor in the contralateral kidney is between 5% and 33%, depending on the type of nephroblastomatosis that is present. Pathological examination shows nephroblastomatosis in about one-fourth of kidneys removed for Wilms tumor.

Multifocal perilobar nephroblastomatosis is the most common form. This type tends to occur in association with various syndromes that are associated with Wilms tumor, such as hemihypertrophy and BWS. This type of nephroblastomatosis is present in nearly all children with bilateral Wilms tumors. Multifocal perilobar nephroblastomatosis is the most common form of nephroblastomatosis to be identified in grossly uninvolved parenchyma of a kidney removed for Wilms tumor. The histological appearance is that of multiple subcapsular foci of persistent mesonephric tissue. Children with this finding tend to be older than typical Wilms tumor patients. There are 3 subtypes of multifocal nephroblastomatosis. More than 1 of the 3 subtypes of multifocal nephroblastomatosis can coexist in the same kidney.

The nodular renal blastema subtype of multifocal perilobar nephroblastomatosis is characterized by the presence of multiple aggregates of residual mesonephric blastema in the subcapsular glomerulogenic zone. These foci are usually less than 300 μm in diameter. These blastema cells are histologically similar to those found in Wilms tumor, although necrosis and excessive mitosis are lacking. The prevalence of nodular renal blastema in the kidney contralateral to a Wilms tumor is approximately 10%. This type of nephroblastomatosis occurs in some patients with trisomy 18, trisomy 13, or congenital heart disease. Demonstration of this finding in a kidney removed for Wilms tumor indicates a small elevation in risk for eventual development of a Wilms tumor in the remaining kidney.

Metanephric hamartoma is a subtype of multifocal perilobar nephroblastomatosis that consists of small, circumscribed superficial foci that originate from nodular renal blastema. Histological examination shows fibrous tissue and collagenous tissue. The foci ranged from 1 to 30 mm in diameter. This lesion is associated with a slightly elevated risk for the development of Wilms tumor.