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AFIP ARCHIVES

Best Cases from the AFIP

Wilms Tumor in the Setting of Bilateral Nephroblastomatosis1 Ami Trivedi Sethi, MD • Lakshmana Das Narla, MD • Sarah J. Fitch, MD • William J. Frable, MD

Figure 1.  Axial contrast-enhanced CT images of the abdomen (a) and pelvis (b) show the abnormally enlarged kidneys and a thick rim of plaquelike blastemal tissue, which demonstrates a lack of enhancement. The cortical tissue demonstrates normal enhancement and is compressed by peripheral nephroblatomatosis rests. The right kidney is affected to a greater degree than the left.

History

A 6-month-old African-American girl presented with a hard abdominal mass, a finding corroborated by her primary care physician. Until that point, she was healthy, and all developmental milestones were reached. The mother underwent a normal pregnancy and unremarkable vaginal delivery, and there was no history of chronic disease. Computed tomography (CT) and biopsy were performed, and a diagnosis of nephroblastomatosis was made. Follow-up serial abdominal magnetic resonance (MR) imaging was performed.

Imaging Findings

Initial oral and intravenous contrast material–enhanced abdominopelvic CT was performed on a 64-detector scanner (Somatom 64; Siemens,

Forchheim, Germany) with the following parameters: 3-mm section thickness, pitch of 1.5, 90 mA, and 140 kVp; intravenous contrast material (Omnipaque 300; GE Healthcare, Princeton, NJ) was administered with a hand bolus at a rate of 1 mL per pound of body weight. The kidneys were abnormally enlarged, and multiple plaquelike peripheral lesions of cortical tissue, which did not enhance substantially relative to renal tissue, were present (Fig l). No hydronephrosis, renal calcifications, focal round mass, or necrotic mass was seen. The right kidney was afflicted to a greater degree than the left. When the patient was 18 months old, MR imaging (Avanto; Siemens, Erlangen, Germany) was performed with the use of a body coil for

RadioGraphics 2010; 30:1421–1425 • Published online 10.1148/rg.305095022 • Content Codes: From the Departments of Radiology (A.T.S.), Pediatric Radiology (L.D.N., S.J.F.), and Pathology (W.J.F.), Virginia Commonwealth University and Medical College of  Virginia Hospitals, 1250 E Marshall St, PO Box 980615, Richmond, VA 23298-0615. Received February 10, 2009; revision requested March 20 and received April 16, 2010; final version accepted April 22. All authors have no financial relationships to disclose. Address correspondence to L.D.N. (e-mail: [email protected]). 1

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Figure 2.  Axial T2-weighted MR image shows the bilaterally enlarged kidneys and the thickened cortex. Scalloped, lowsignal-intensity peripheral blastemal tissue also is seen compressing the renal parenchyma, which demonstrates central enhancement.

Figure 3.  Unenhanced axial (a, b) and coronal (c) T1-weighted MR images show a somewhat round, heterogeneous lobulated mass in the inferior pole of the right kidney. No areas of fat are seen within the mass, which demonstrated minimal enhancement on contrast-enhanced images (not pictured).

6-month surveillance. Both kidneys demonstrated bilateral enlargement, and a heterogeneous round focal mass was seen in the inferior right renal cortex. The mass exhibited high signal intensity and minimal enhancement on T2-weighted images, and it demonstrated predominantly low signal intensity on T1-weighted images (Figs 2, 3). Compared with previous MR imaging evaluations, the mass demonstrated an increase in size, a finding indicative of a neoplastic process. No suspicious mass was seen in the contralateral kidney, and no lymphadenopathy, renal vein thrombosis, or distant solid-organ metastases were noted.

Pathologic Evaluation

Right nephrectomy was performed, and a soft friable 5.1-cm lobulated mass was seen in the lower pole of the kidney abutting the capsule posteriorly (Fig 4). At histologic analysis, extensive cortical expansion and heterogeneity were

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Figure 5.  Photomicrograph (original magnification, ×1; hematoxylin-eosin stain) shows persistent embryogenic renal tissue and a sharply demarcated lobular softtissue mass inferiorly, findings indicative of nephroblastomatosis with a predominant Wilms tumor.

Figure 4.  Photographs of the resected kidney show cortical expansion and heterogeneity, findings indicative of hyperplastic perilobular nephroblastomatosis. A lobulated, friable mass also is seen in the lower pole, abutting the cortex. Scales are in centimeters.

seen, findings consistent with diffuse hyperplastic perilobular nephroblastomatosis (Fig 5). No additional multicentric tumor foci were noted, and the renal capsule was intact. A diagnosis of stage 1 blastema with a predominant Wilms tumor was made.

Discussion

Embryologic development of the kidneys begins at 5 weeks gestation, when the ureteral bud forms the renal pelvis and calices. The tissue surrounding the ureteral bud is called metanephric blastema, which forms nephrons. This tissue eventually becomes the renal cortex and the Bertin columns, which surround the medullary kidney. Nephrogenesis is complete by weeks 35–36 of gestation (1,2). Metanephric blastema that persists at birth is called a nephrogenic rest; multiple nephrogenic

rests are referred to as nephroblastomatosis. According to autopsy studies, evidence of nephrogenic rests, which indicate a lack of progression of fetal tissue to normal renal parenchyma, is present in approximately 1% of infants. Malignant transformation occurs in less than 1% of children with a nephrogenic rest (2). Beckwith (3) divided nephrogenic rests into two groups: intralobar, those that occur anywhere within the lobe, and perilobar, those that occur in the cortex covering the lobe. Although these two types of rests derive from the same tissue, their typical appearances, malignant potential, and associated syndromes are different. Perilobar rests are more common than intralobar rests and usually are multiple and well circumscribed. Intralobar rests are irregular and usually occur singly or in a small number. At histologic analysis, stromal or epithelial tissue predominates in intralobar rests, whereas blastemal tissue predominates in perilobar rests. Intralobar rests manifest at an earlier age (mean, 1.6 years) than do perilobar rests (mean, 3.6 years). Perilobar rests are associated with Beckwith-Wiedemann syndrome (gigantism, macroglossia, omphalocele, and genitourinary anomalies) and hemihypertrophy. Intralobar rests are associated with Drash syndrome (ambiguous genitalia and progressive renal failure

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in boys) and sporadic aniridia; Wilms tumor is more commonly associated with intralobar rests than with perilobar rests (1,2). Beckwith (3) further categorized rests, on the basis of histologic analysis, as dormant (nascent), sclerosing, hyperplastic, and neoplastic. The dormant and sclerosing subtypes rarely progress to Wilms tumor and are not considered to be premalignant. However, none of these subtypes is stagnant, and they may progress to the neoplastic type. For this reason, close follow-up is recommended. It may be difficult to differentiate between the hyperplastic and neoplastic subtypes. Pathologists can differentiate between Wilms tumor and nephroblastomatosis because Wilms tumor tends to grow in the form of a sphere and develops a pseudocapsule, unlike the rests seen in nephroblastomatosis. The use of needle biopsy is insufficient to differentiate between these two conditions, and children are treated on the basis of imaging findings (4). At gross inspection, only the hyperplastic and neoplastic forms appear as tan nodules against a background of normal renal tissue. The dormant and sclerosing types are visible only at microscopic analysis. The imaging appearances of focal areas of nephroblastomatosis range from well-demarcated to ill-defined nodules, depending on the subtype. At CT, the nodules usually are hypo- to isoattenuating, and they demonstrate little or no enhancement compared with normal renal tissue. At ultrasonography (US), the renal shape is distorted, and the nodules are hypo- to isoechoic; however, it may be difficult to appreciate these nodules as distinct abnormalities. For this reason, CT is the modality of choice. At MR imaging, the foci are hypo- to isointense on T1-weighted images and they demonstrate variable signal intensity with little or no enhancement on T2-weighted images. The intralobar type is more irregular than the perilobar type, which is easier to identify at imaging. At MR imaging, corticomedullary differentiation is absent, and the kidneys usually are enlarged with a peripheral, well-demarcated rind of tissue (5). Nephroblastomatosis is more homogeneous than Wilms tumor at all imaging modalities. The presence of a distinct developing or enlarging mass, especially a heterogeneous mass, is indicative of Wilms tumor. Although most children with nephroblastomatosis do not develop Wilms tumor, it is associated with perilobar rests, and 4%–5% of patients

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with intralobar rests are at risk for development of Wilms tumor. It is currently believed that approximately 30%–40% of Wilms tumors arise from nephrogenic rests, which are found in as many as 99% of patients with bilateral Wilms tumors (1,5). If the hyperplastic form of nephroblastomatosis is present, chemotherapy may be administered to decrease the size of the rests and prevent potential neoplastic transformation; however, this treatment method is controversial. Some advocate the removal of any new or growing mass because of the difficulty in distinguishing between the hyperplastic and neoplastic forms of nephroblastomatosis. A new, enlarging, or heterogeneous mass in the setting of nephroblastomatosis is indicative of Wilms tumor, and any patient with a Wilms tumor and a nephrogenic rest is at risk for development of Wilms tumor in the contralateral kidney (5,6). Screening is recommended at 3-month intervals for children at high risk for Wilms tumor or with nephroblastomatosis. MR imaging is the method of choice for follow up; however, some authors recommend alternating MR imaging and US to reduce both cost and the use of deep sedation or anesthesia. Despite its low sensitivity for delineating foci of nephroblastomatosis, US can demonstrate a round focal mass, a finding suggestive of Wilms tumor. Wilms tumor is the most common malignant abdominal tumor among children, accounting for more than 70% of pediatric renal masses. In most children, Wilms tumor manifests between 6 months and 5 years of age. The overall survival rate exceeds 85%; however, survival is impaired in those with an unfavorable histologic subtype or synchronous bilateral Wilms tumors (7). The pathogenesis of Wilms tumor is complex and multifactorial. Although nephrogenic rests are a predisposing condition for the development of Wilms tumor, not all kidneys with nephrogenic rests develop Wilms tumor. For example, among kidneys removed for Wilms tumor, more than 40% contained nephrogenic rests outside the tumorous area. Genetic mutations of chromosome 11 have been described in patients with Wilms tumor. An abnormal WT1 gene (a specific locus of chromosome 11) has been found in patients with WAGR syndrome (Wilms tumor with aniridia, genitourinary abnormalities, and mental retardation), and an abnormal WT2 gene has been found in patients with Beckwith-Wiedemann syndrome (macroglossia, omphalocele, and genitourinary anomalies) and hemihypertrophy. A small

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subset of Wilms tumors (1%) are familial and have no association with chromosome 11. Other associated syndromes and conditions that increase the risk for Wilms tumor include Perlman syndrome, Drash syndrome, aniridia, genitourinary tract anomalies, cryptorchidism, renal hypoplasia, and horseshoe kidney (8,9). At histologic analysis, the appearance of Wilms tumors varies, a result of a mixed composition of blastemal, stromal, and epithelial tissue. Eightyfive percent of Wilms tumors demonstrate this “triphasic” composition. Anaplasia, recognizable by abnormally large nuclei, indicates an unfavorable histologic subtype and is associated with a poor outcome. Patients with anaplasia tend to be older than those without anaplasia, and they have a higher rate of metastases and an increased resistance to chemotherapy. Fortunately, approximately 90%–95% of patients have a favorable histologic subtype, which has an excellent prognosis, even at advanced stages (8,10). Imaging findings of Wilms tumor vary depending on the amount of necrosis, hemorrhage, calcification, fat, and cystlike formation present; however, a well-defined solid mass with a pseudocapsule usually is seen. The mass distorts renal parenchyma, leading to a rind or “claw” of renal tissue surrounding the tumor, a finding that helps distinguish Wilms tumor from neuroblastoma. Wilms tumor may invade the surrounding renal vein (the inferior vena cava), with possible extension into the right atrium. It is bilateral in an estimated 6%–13% of affected children, and it is multifocal in one kidney in 12% of affected children (9,11). When metastases are present they are found in the lungs, lymph nodes, liver, and, occasionally, the retroperitoneum (9–11). Treatment of Wilms tumor depends on several factors including the patient’s age at the time of onset, the size and extent of the tumor, and whether the histologic subtype is favorable or unfavorable. Favorable stage 1 and stage 2 Wilms tumors are treated with nephrectomy and chemotherapy. Abdominal radiation therapy is added for stage 3 and stage 4 disease. Preoperative chemotherapy is performed in patients with stage 5 disease and in those with a large tumor. Partial nephrectomy typically is not performed. Treatment of unfavorable Wilms tumors includes radiation therapy and preoperative chemotheraphy. When bilateral Wilms tumors are present, each side is staged separately and kidney-sparing surgery is performed (6,7). Many patients are

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now diagnosed at biopsy and treated with chemotherapy before surgical resection (12). In our case, the patient underwent right nephrectomy and was treated with a chemotherapeutic regimen of vincristine, actinomycin-D, and doxorubicin. Recent MR imaging revealed progression of nephroblastomatosis in the remaining kidney and development of a new focal mass that was suspicious for Wilms tumor. The patient underwent more aggressive chemotherapy, which resulted in a rapid reduction in size of the focal mass and peripheral lesions. These lesions likely were due to nephrogenic rests. Follow-up MR imaging demonstrated no lymphadenopathy or distant metastases.

References 1. White KS, Kirks DR, Bove KE. Imaging of nephroblastomatosis: an overview. Radiology 1992;182(1): 1–5. 2. Lonergan GJ, Martínez-León MI, Agrons GA, Montemarano H, Suarez ES. Nephrogenic rests, nephroblastomatosis, and associated lesions of the kidney. RadioGraphics 1998;18(4):947–968. 3. Beckwith JB. Nephrogenic rests and the pathogenesis of Wilms tumor: developmental and clinical considerations. Am J Med Genet 1998;79(4):268–273. 4. Murphy WM, Grignon DJ, Perlman EJ. AFIP Atlas of tumor pathology, series 4: tumors of the kidney, bladder and related structures. Washington, DC: American Registry of Pathology, 2004. 5. Rohrschneider WK, Weirich A, Rieden K, Darge K, Tröger J, Graf NUS. US, CT and MR imaging characteristics of nephroblastomatosis. Pediatr Radiol 1998;28(6):435–443. 6. Prasil P, Laberge JM, Bond M, et al. Management decisions in children with nephroblastomatosis. Med Pediatr Oncol 2000;35(4):429–432; discussion 433. 7. Kalapurakal JA, Dome JS, Perlman EJ, et al. Management of Wilms’ tumour: current practice and future goals. Lancet Oncol 2004;5(1):37–46. 8. Lowe LH, Isuani BH, Heller RM, et al. Pediatric renal masses: Wilms tumor and beyond. RadioGraphics 2000;20(6):1585–1603. 9. Siegel MJ, Chung EM. Wilms’ tumor and other pediatric renal masses. Magn Reson Imaging Clin N Am 2008;16(3):479–497, vi. 10. Aquisto TM, Yost R, Marshall KW. Anaplastic Wilms tumor: radiologic and pathologic findings. RadioGraphics 2004;24(6):1709–1713. 11. Meyer JS, Harty MP, Khademian Z. Imaging of neuroblastoma and Wilms’ tumor. Magn Reson Imaging Clin N Am 2002;10(2):275–302. 12. Neville HL, Ritchey ML. Wilms’ tumor: overview of National Wilms’ Tumor Study Group results. Urol Clin North Am 2000;27(3):435–442.