The majority of Wilms’ tumors form isolated, well-demarcated masses separated from the adjacent kidney (Fig. 10.2) [1, 8]. Rarely, a botryoid variant of Wilms’ tumor is seen, characterized by polypoid mass occupying the renal pelvis (Fig. 10.3). After preoperative chemotherapy, significant amounts of necrosis or hemorrhage can occur. Cystic lesions require careful inspection for nodular solid areas [8].

Histology is an important prognostic indicator for Wilms’ tumor. Certain histologies, particularly anaplastic Wilms’ tumors, show higher risks of tumor recurrence or chemotherapy resistance [1]. Traditional Wilms’ tumors contain varying amounts of three basic histological components—blastemal, epithelial, and stromal cells—which vary widely in relative proportions (Fig. 10.4) [7, 8]. If one component comprises >2/3 of a tumor, it is referred to as predominant for that specific cell type [7].

Blastemal predominant Wilms’ tumors are generally more aggressive, i.e., higher stage, but usually respond to stage-specific therapy [10]. They contain sheets of small, round-to-ovoid cells with irregular nuclei, small nucleoli, and little cytoplasm, usually with mitotic figures, apoptotic bodies, and closely packed, overlapping nuclei with diffuse chromatin (Fig. 10.5) [8]. On occasion, rosette formation may resemble neuroblastoma. Growth patterns lack prognostic significance and include diffuse, serpentine, nodular, and basaloid features [7, 8].

Epithelial predominant Wilms’ tumor is less aggressive but may be resistant to therapy with advanced stage [10]. It is composed of rosette-like and glomeruloid tubules lined by low columnar cells with hyperchromatic nuclei and papillary intratubular invaginations (Fig. 10.6) [7, 8]. Mucinous and squamous epithelium, neural structures, and neuroendocrine cells may also be seen [7]. With epithelial predominant Wilms’ tumor, one should exclude metanephric adenoma (MA), a rare benign tumor that accounts for ~0.2–1 % of all kidney tumors [19]. MAs occur at all ages, ranging 5–80 but most commonly 40–60 years old [8, 20]. Up to 12 % of MA patients have polycythemia [21]. They are purely epithelial lesions lacking stroma and containing densely packed uniform ovoid cells with even, lymphocyte-like nuclei forming a tubular pattern, pink to clear cytoplasm and frequent psammoma bodies. Unlike Wilms’ tumors, MAs contain extremely rare to absent mitoses [21], and show little or no compression of adjacent renal tissue. Metanephric adenofibromas contain both stromal and epithelial components but occur extremely rarely (only 25 cases in the NWTS series [22, 23]).

Stromal predominant Wilms’ tumors, like epithelial-predominant ones, show poor clinical responses to chemotherapy [10]. They may contain hypocellular, sparse regions of immature stellate cells in a myxoid background and dense areas of primitive spindled mesenchymal cells. Other stromal cell types include smooth and striated muscle (Fig. 10.7a), adipose tissue, cartilage (Fig. 10.7b), bone, and osteoid, with muscle representing the most common differentiated stromal cell type [7, 8]. It is important in bone forming lesions to consider ossifying renal tumor of infancy, an extremely rare pediatric renal neoplasm with a benign clinical course [23]. With stromal lesions, one should also consider metanephric stromal tumor (MST), an extremely rare, entirely stromal lesion in the spectrum of metanephric neoplasms. Most MSTs occur in the first decade of life [8, 25, 26]. Characteristic concentric “onion skin” rings are observed surrounding entrapped renal tubules or blood vessels. These rings or collarettes are the most defining histological characteristic of MST.

Anaplasia is the major unfavorable histological variant of Wilms’ tumors and accounts for 5–10 % of unilateral Wilms’ tumors [1, 8, 10]. It rarely occurs in children under 2 but peaks at about 5 years of age [7, 11]. It is more common in African-American that Caucasian patients [11]. Anaplasia is defined by atypical multipolar mitotic figures, hyperchromatism, and enlarged tumor nuclei at least three times the size of adjacent ones (Fig. 10.8). Anaplasia may be focal or diffuse. With focal anaplasia, only one or two isolated intrarenal foci show anaplastic changes. Diffuse anaplasia occurs in extrarenal or multiple intrarenal locations. In stages higher than stage I, diffuse anaplasia has a significantly worse prognosis and is chemotherapy-resistant [7, 8].

Immunohistochemistry has a minor role in diagnosis of nephroblastomas, since the major diagnostic tool lies in tumor morphology. However, it can be helpful with needle core biopsies containing small round cell tumor. WT1, the most helpful marker, is expressed by nuclei of both blastemal and primitive epithelial cells. Primitive renal blastema also shows diffuse and strong but nonspecific positivity for CD56. Nuclear p53 expression has been reported in most anaplastic Wilms’ tumors [8].

Various genes have been implicated in hereditary and syndromic Wilms’ tumor. One to 3 % of patients have a family history of inherited tumors [1, 9]. Genetically inherited cases tend to have an earlier onset and increased bilaterality [10]. Two familial genes have been specified: FWT1 at 17q12-q21 and FWT2 at 19q13 [10]. About 10 % of Wilms’ tumor patients show associated congenital abnormalities and syndromes. Mutations of Wilms’ tumor 1 (WT1), a tumor suppressor gene located at 11p13, occur in the Wilms’ tumor, aniridia, genitourinary anomalies, mental retardation (WAGR), and Denys–Drash (DDS) syndromes (Fig. 10.9) [9]. WT1 encodes a transcription factor important in gonadal development, ureteric budding, and nephrogenesis [1]. WAGR and DDS patients have increased risk of bilateral tumors, younger age, and renal dysfunction [10]. WT1 mutations also occur in about 2 % of sporadic tumors [10].

Aniridia is a non-overgrowth syndrome found in 1.1 % of Wilms’ tumor patients. It is caused by a defect in the PAX6 gene located at 11p13 adjacent to WT1. About 40–70 % of aniridia patients have a contiguous WT1 deletion causing Wilms’ tumor [1, 10]. In addition, more than half of tumors with WT1 mutations have coexisting ones in the beta-catenin gene (CTNNB1), suggesting involvement of the Wnt/beta-catenin pathway, and mutations in this gene are found in 5–15 % of Wilms’ tumors overall [9, 10].

Loss of heterozygosity (LOH) of the Wilms’ tumor 2 (WT2) gene locus located on chromosome 11p15 has been identified in up to 40 % of sporadic cases and 1–8 % of Beckwith–Wiedemann syndrome (BWS) patients [9]. BWS patients with hemihypertrophy have a 4–10 % chance of developing Wilms’ tumors, 21 % of them bilateral [1, 10]. Specific genes located within the WT2 domain include H19 and insulin-like growth factor 2 (IGF2) [10]. Differential DNA methylation of these two genes reveals biallelic expression of IGF2 in 26–77 % and hypermethylation of H19 in 26–75 % of Wilms’ tumors without LOH [9].

Wilms’ tumors show LOH at chromosomes 16q and 1p in 20 % and 10 % of cases, respectively. LOH at these locations increases the risk of tumor relapse and mortality [1, 10]. Lesions that have LOH at both 16q and 1p show an even greater propensity for relapse and mortality, with the relapse-free rate dropping to 74.9 % (in combination) from 80.4 % (1p alone) and 82.5 % (16q alone) [27]. LOH at 11q occurs in 20 % of Wilms’ tumors and is three to four times more common in anaplastic ones [10].

The Wilms’ tumor gene on the X chromosome (WTX) on Xq11.1 is activated in up to one third of Wilms’ tumors, affecting the single X in males or the active X in females as a “single hit,” or monoallelic, event. WTX is thought to be involved in the Wnt/beta-catenin signaling pathway [1, 10].

Recent advancements in imaging technology have greatly facilitated the detection of small renal tumors and nephrogenic rests. Both contrast enhanced CT and contrast enhanced MRI can detect nephrogenic rests as small as 4–5 mm, so routine intraoperative exploration of the contralateral kidney is no longer recommended [38].

Because US is widely available and relatively inexpensive, it is the primary imaging method for screening patients at risk of nephrogenic rests. On US, NR lesions are typically homogeneous and hypoechoic or isoechoic to normal kidney tissue. As nephrogenic rests are relatively less vascular than normal renal parenchyma, use of power Doppler imaging can aid in the detection of nephrogenic rests. Ultrasonography can detect NR as small as 8 mm, but has a lower sensitivity than CT or MRI [18, 39, 40]. On CT, nephrogenic rests are most evident on post contrast images as homogeneous lesions that enhance less than the normal renal parenchyma. On MR, hyperplastic rests are relatively T2 hyperintense compared to normal renal parenchyma, while sclerotic rests are relatively hypointense on T2 weighted images [39]. As on CT, nephrogenic rests enhance less than normal renal parenchyma on post contrast MR images.

Imaging differentiation of nephrogenic rests from Wilms’ tumor can be difficult. While nephrogenic rests tend to have a more homogeneous appearance on all imaging modalities, heterogeneity favors Wilms’ tumor. Both tumor and hyperplastic rests tend to be bright on T2-weighted images [39]. The size of the lesion per se is not reliable for differentiation, as nephrogenic rests up to 5 cm in diameter have been reported [18].

The presence of multiple bilateral nephrogenic rests is referred to as nephroblastomatosis (Fig. 10.10a, b) [41]. A specific subtype of nephroblastomatosis is diffuse hyperplastic perilobar nephroblastomatosis (DHPLN), characterized by a rind of nephroblastic tissue surrounding the renal parenchyma (Fig. 10.11). On imaging the kidneys are diffusely enlarged but maintain their normal reniform shape. The nephroblastic rind is confined to the periphery of the kidney, has homogeneous attenuation/signal intensity, and enhances less than the normal kidney.

Nephroblastomatosis should be distinguished from renal lymphoma, which can also result in bilateral renal masses. Children with nephroblastomatosis are younger (<5 years of age) and lack the extensive retroperitoneal lymphadenopathy usually seen in patients with lymphomatous involvement of the kidneys.

Cystic nephroma and cystic partially differentiated nephroblastoma are relatively uncommon benign lesions that are indistinguishable on imaging [46]. They are typically solitary, multilocular lesions sharply demarcated from an otherwise normal remaining kidney. The masses are usually large, averaging 8–10 cm in size, and involve only part of the kidney. These are multicystic lesions, and with no solid nodules, that may protrude into the renal pelvis/ureter. On sonography, the mass consists of multiple anechoic cystic areas separated by septations (Fig. 10.12a, b). These cystic areas can vary in size from microscopic to 4 cm in diameter. The microcystic areas may mimic solid areas due to the closely packed septations. On CT and MRI, CN and CPDN typically appear as well circumscribed, multicystic masses that have variable enhancement of septations on the post contrast images. The septations are typically hypointense on precontrast T1 and T2 weighted images due to fibrous tissue in them. The differential diagnosis of a multilocular cystic renal mass in a child includes cystic Wilms’ tumor or renal cell carcinoma; clear cell sarcoma; cystic variants of mesoblastic nephroma; and segmental forms of multicystic dysplastic kidney. The presence of solid components within a cystic mass should make one consider a diagnosis other cystic nephroma/cystic partially differentiated nephroblastoma. If a cystic pulmonary lesion is identified in a child with a multicystic renal mass, this should lead one to consider a DICER 1 mutation with cystic nephroma and coexistent pleuropulmonary blastoma [47].

Although CMN only represents less than 5 % of all pediatric renal neoplasms, it is the most common congenital renal tumor, with over 90 % of patients diagnosed before age 1 and almost no patients presenting after the age of 3. The cellular variant represents approximately 40–60 % of CMN, with the classical and mixed subtypes constituting the remaining percentage with about an equal prevalence [8, 48].

The majority of renal tumors diagnosed within the first 6 months of life are CMN, so it must be included in the differential diagnosis of any infant with a renal mass. Because its incidence drops off significantly after early childhood, diagnosis of any spindle cell tumor as CMN must be questioned in patients older than 3 years. There does not appear to be any definitive gender predisposition, but some studies report a slight male prevalence [49, 50]. The general median age of diagnosis is approximately 20–35 days, with the cellular type (median: 3–4 months) being diagnosed at a significantly older age than the classic (median: 7 days) or mixed (median: 2 months) variants [49, 50].

Most patients present with an asymptomatic abdominal mass discovered upon physical examination or after imaging analysis. Other symptoms include abdominal swelling and protrusion, abdominal pain, hypertension, hypercalcemia, and hematuria [48, 50, 51]. These tumors may cause polyhydramnios during pregnancy, requiring preterm delivery in a reported 71 % of CMN associated fetuses [48].

Grossly, the tumor is usually solid but rarely can have a prominent cystic appearance. Congenital mesoblastic nephroma tend to be firm pale to tan-colored lesions (Fig. 10.14), with the cellular variant being softer and more likely to demonstrate necrosis or hemorrhage than the classic variant. The mixed subtype shows both characteristics. The tumor often infiltrates normal adjacent renal parenchyma and perinephric fat. As previously mentioned, the cellular type is usually much larger in volume than the mixed or classic types [7, 8, 48].

Histologically, classic CMN demonstrates morphology similar to that of uterine leiomyoma and infantile fibromatosis; it contains bundled spindle cells, infrequent mitosis, and absence of necrosis (Fig. 10.15a). The spindle cells lie within collagenous stroma, show an interlacing fascicular pattern, and infiltrate surrounding renal parenchyma as finger-like projections. The cellular variant has a more malignant appearance, with an increased nuclear: cytoplasmic ratio, cellularity, and mitotic index and significantly more necrosis and hemorrhage (Fig. 10.15b). CMNs lack the blastemal components observed in Wilms’ tumor and do not demonstrate characteristic vascular patterns, nuclear grooves, or clear cells as seen in clear cell sarcoma of the kidney [8, 51, 52]. However, they often entrap renal tubular elements, which may show atypia.

The most common immunohistochemical characteristic of CMN is diffuse nonspecific reactivity for vimentin and focal reactivity for smooth muscle actin [8, 51]. The tumor usually does not show immunoreactivity for desmin, S-100, cytokeratin, AE1/AE3, epithelial membrane antigen, bcl-2, or CD99 [51, 54].

Recent cytogenetic studies have found strong genetic correlations between the cellular variant of CMN and congenital infantile fibrosarcoma (CFS). Using RT-PCR and fluorescence in situ hybridization, a study found that five out of six cellular CMN tumors and five out of five CFS tumors tested were found with the same t(12;15)(p13;q25) translocation that resulted in a ETV6-NTRK3 (aka TEL-NTRK3) gene fusion [55]. Both of these entities have also been associated with genetic polysomies at chromosomes 8, 11, 17, and 20 [55, 56], with trisomy 11 being strongly correlated with CMN. Because cellular CMN and CFS have similar histological and morphologic features and the same genetic abnormalities, these two neoplasms appear to represent the same entity, with cellular CMN being the renal variant. Additionally, it has been reported that primary bronchopulmonary fibrosarcoma (BPFS), a rare lower respiratory neoplasm affecting children and young adults, also carries the t(12;15) ETV6-NTRK3 genetic abnormality [55, 57]. Thus, we consider CMN and BPFS as visceral variants of CFS. The same t(12;15) ETV6-NTRK3 fusion does not appear with classic CMN, which may be found in conjunction with cellular CMN in the mixed subtype. ETV6-NTRK3 fusion is also found in a dissimilar tumor, secretory carcinoma of the breast [55].

Grossly, CCSKs are large, soft, and gray-tan to white in appearance. They are uniform, fleshy, well circumscribed, sharply demarcated, and almost always present unilaterally in the kidneys. Tumors are usually solid but may be focally cystic with necrosis and hemorrhage [7, 8, 54, 63]. The tumors often involve renal medulla and may replace and distort the entire kidney [7, 59]. Renal vein invasion occurs in approximately 5 % of cases [59, 60]. Tumors measure between 2.3 and 24 cm [60].

Perhaps the most diagnostically difficult aspect of CCSK is its histological variability: nine variations have been described [59, 60]. The classic pattern contains cords or nests of ovoid, epithelioid, and spindle shaped cells separated by consistently spaced fibrovascular septa [67, 60]. These septa characteristically feature branching or “chicken-wire” capillaries that vary in width. Tumor nuclei are uniform in shape, and their cytoplasm is clear to pale with an ill-defined cell border (Fig. 10.16) [60, 63]. Although over 90 % of CCSK predominately or focally demonstrate the classic pattern, most also present one of the other eight identified histologic variants, percentages: myxoid (50 %), sclerosing (35 %), cellular (26 %), epithelioid (13 %), palisading (11 %), spindle cell (7 %), storiform (4 %), and anaplastic (2.6 %) [60]. The different patterns are essentially varying alterations of the cord/nest or septal cell appearance, and they therefore cannot be separated as distinct biological entities.