Pediatric Renal Tumors

Gross Features

WT typically presents as a unicentric, spherical mass that is sharply demarcated from the renal parenchyma. Approximately 10% of WTs are multicentric, a finding that is associated with an increased likelihood of WT formation in the contralateral kidney. Approximately 5% to 6% of WTs are bilateral at presentation.

The cut surface of WT is generally pale gray and uniform, but hemorrhage, necrosis, and cyst formation are common. The texture is usually soft and friable, but stroma-rich neoplasms may have a dense, myomatous consistency. Calcification is relatively uncommon. Prominent septa frequently impart a multinodular app­earance.

WT may arise anywhere in the cortex or medulla, frequently compressing and distorting renal parenchyma around its margin. Rarely exophytic tumors connected to the renal surface by a narrow stalk mimic extrarenal WT. Polypoid masses in the pelvicalyceal lumen may occur either as extensions from the primary intrarenal neoplasm or as separate neoplasms arising within the pelvic wall. The renal vein and its branches not uncommonly are filled by tumor thrombus that can extend via the inferior vena cava into the right atrium.

Cystic Variants of Wilms Tumor

Scattered cysts are commonly encountered in conventional WT, but rarely the encapsulated, well-delineated neoplasm is composed entirely of cystic spaces and delicate septa, without an expansile solid component. For neoplasms that are entirely composed of mature cells, the term is cystic nephroma (CN). If the septa contain embryonal cell types, the designation cystic, partially differentiated nephroblastoma (CPDN) is appropriate. In contrast, cystic WT is distinguished by the presence of solid, expansile regions that replace or distort the cystic spaces, rather than being passively molded by the cysts. This distinction is best made by careful examination of the gross specimen.

CPDN has traditionally been thought to be a transitional stage in a continuum ranging from CN to WT. However recent studies show that CN is associated with DICER1 mutations, whereas such mutations are not observed in CPDN. This suggests that the two cystic renal tumors are distinct entities. The distinction of CN from CPDN has little clinical importance when the lesion has been completely resected because both lesions are curable by resection alone.

Microscopic Features

WTs are surpassed only by teratomas in their diversity of cell and tissue types and degrees of differentiation. Most WTs exhibit, at least focally, the so-called triphasic appearance, including cells of blastemal, stromal, and epithelial lineage ( Fig. 55-1 ). However monophasic and biphasic WTs are relatively common, consisting of only one or two of these cell lineages. Each of the three major cell types can demonstrate a spectrum of patterns and degrees of differentiation, accounting for the remarkable diversity of appearances characterizing various WTs.

Blastemal Patterns.

The blastemal cells of WT are small, tightly packed cells with a high nucleus-to-cytoplasm ratio, demonstrating little or no evidence of differentiation toward epithelial or stromal cell types at the light-microscopic level. Their nuclei are usually round or oval, with moderately coarse chromatin, and mold to one another in the same fashion as do the nuclei of small cell carcinoma of the lung. Nucleoli are relatively inconspicuous. Blastemal cells form several distinctive aggregation patterns, which can be divided into two broad categories, diffuse and nested, depending on their structure and degree of invasiveness. Monomorphous, relatively dyscohesive sheets of blastemal cells with aggressively invasive margins characterize the diffuse blastemal pattern. This is the most consistently aggressive pattern of WT. Stage I WTs rarely show this pattern; the majority of diffuse blastemal WT present at advanced stage, stage III or IV. Fortunately most neoplasms with the diffuse blastemal pattern are highly responsive to modern therapeutic protocols, so this pattern remains in the “favorable histology” category. The diffuse blastemal pattern can be readily confused with other small blue cell tumors of childhood, and ultrastructural or other special studies may be required to establish the correct diagnosis ( Fig. 55-2 ).

Nested blastemal patterns are characterized by sharply outlined clusters of blastemal cells in a myxoid mesenchymal background. They usually lack the invasive behavior seen with the diffuse blastemal pattern, and these neoplasms have sharply defined margins at their advancing edge. Several nested patterns may be seen. The serpentine blastemal pattern features long, serpiginous, anastomosing cords of blastemal cells in a loose, stellate, spindled stroma. This is a highly distinctive pattern of WT and helps distinguish WT from other small blue cell neoplasms of childhood. The nodular blastemal pattern resembles the serpentine pattern but has rounded blastemal nests instead of long cell cords. The basaloid blastemal pattern resembles the serpentine or nodular patterns, except that the blastemal cell clusters are outlined by a palisaded layer of cuboidal or columnar cells, reminiscent of the architecture of cutaneous basal cell carcinoma.

Anaplasia: the Sign of Unfavorable Histology in Wilms Tumor

Approximately 5% of WTs demonstrate anaplastic nuclear change, the only criterion of “unfavorable histology.” All WTs lacking this feature are designated as having “favorable histology.” Anaplasia is almost never seen in WT diagnosed during the first year and is rare in the second year of life. The relative frequency of anaplasia increases after that age, and it is found in approximately 10% of WTs diagnosed after the age of 5 years. Anaplastic nuclear change reflects extreme polyploidy and is usually apparent under low magnification (10× objective). The features of anaplasia include (a) markedly enlarged tumor cell nuclei with increased chromatin content (hyperchromasia) and (b) multipolar mitotic figures ( Fig. 55-3 ). The former criteria reflect polyploidy, whereas the latter criterion helps exclude degenerative nuclear changes, as are commonly seen in cells showing skeletal muscle differentiation, from the anaplastic category. Anaplasia is tightly correlated with the presence of TP53 gene mutations. Whereas favorable-histology WT virtually never harbors TP53 mutations, the majority of anaplastic WTs do. At a practical level, p53 protein overexpression by immunohistochemistry correlates well but not perfectly with morphologically defined anaplasia.

The SIOP Postchemotherapy Histologic Classification System

Patients treated on SIOP studies receive several weeks of chemotherapy before undergoing nephrectomy. Chemotherapy usually affects necrosis of immature and actively proliferating cell types in WT, whereas slowly replicating and differentiated cell types are usually unaffected. For example, tumors composed mostly of mature skeletal muscle or renal tubules show little clinical regression with chemotherapy because so few cells are proliferating. The microscopic appearance of the tumor after chemotherapy has prognostic significance. Approximately 5% to 10% of WTs are completely necrotic after chemotherapy, a finding associated with a 98% 5-year relapse-free survival rate. By contrast, WTs with a predominance of blastemal cells after chemotherapy, defined as viable cells in more than one third of the tumor mass and blastemal cells in at least two thirds of the viable component, have relapse rates of nearly 40%. Based on these observations, the SIOP histologic risk classification schema divides renal tumors into three risk categories: low risk, intermediate risk, and high risk. The COG and SIOP histologic classification systems are compared in Table 55-2 .

Ultrastructural and Immunohistochemical Studies

Ultrastructural study is rarely necessary to establish a diagnosis of WT but can occasionally be very helpful in distinguishing blastemal WT from other undifferentiated neoplasms. The diversity of differentiation in WT creates a correspondingly varied profile of immunohistochemical results. Blastemal cells may or may not label for vimentin and cytokeratin, whereas various differentiating elements will label according to their patterns of differentiation. For example, primitive rhabdomyoblasts within a tumor will label for the myogenic transcription factor myogenin and for cytoskeletal proteins such as actin and desmin. WT blastemal cells characteristically label for desmin but not for actin, myogenin, or other muscle markers. Immunoreactivity for WT1 protein is typically limited to the blastemal and epithelial components of WT, with the stroma being negative. Hence absence of labeling for WT1, particularly in a stroma-rich tumor, does not exclude the diagnosis of WT. Although WT1 immunoreactivity may help distinguish WT from PNET, it should be noted that desmoplastic small round cell tumor typically labels for WT1. Although useful, WT1 immunoreactivity cannot in and of itself establish or disprove a diagnosis of WT.

Nephrogenic Rests and Nephroblastomatosis

In more than 30% of kidneys resected for WT, the renal parenchyma contains one or more regions of persistent embryonal tissue, representing potential precursors of WT. These lesions have been given many names in the past; however, the term suggested by Dr. J. Bruce Beckwith, nephrogenic rests (NRs), is the currently accepted terminology. The presence of multiple or diffusely distributed NRs is called nephroblastomatosis. This term is most commonly applied when the NRs are in an active state of cellular proliferation and are large enough to be apparent on imaging studies.

NRs have a dynamic life history that can yield a variety of appearances. Dr. Beckwith's classification is based on the assumption that the structure of NRs reflects both the dynamic state and the history of an individual rest. A brief summary is provided here.

Two fundamental categories of NRs are recognized, based on their topographic relation to the renal lobe. These are designated perilobar nephrogenic rests (PLNRs) and intralobar nephrogenic rests (ILNRs). ILNRs may occur anywhere in the renal lobe, including the peripheral cortex. They may also occur within the renal sinus, including in the walls of the pelvicalyceal system. ILNR have a more varied structure than do PLNRs and typically intercolate between nephrons, whereas PLNRs usually are discrete structures that are well delineated from adjacent nephrons. Rests of either major category may be further classified on the basis of their developmental fates. An individual NR may undergo any of the following fates, several of which often occur sequentially over time:

• 1.

  It may remain unchanged in size or composition, even for many years, as a tiny, microscopic blastemal focus (dormant NR).

• 2.

  It may undergo maturation, sclerosis, and eventual disappearance (sclerosing NRs and obsolescent NRs). This is the most common fate of NRs.

• 3.

  It may undergo hyperplasia, or coordinated proliferation of all susceptible cells of the rest, as distinguished from a clonal neoplastic process originating in a single cell of the rest. Hyperplastic NR may produce large, actively growing masses that have numerous mitotic figures, and a section from the interior of a hyperplastic NR may be indistinguishable from WT. Several features do help make this distinction. First diffuse hyperplastic growth, involving all or most cells of a rest, tends to preserve the original shape of the rest. When PLNRs form a continuous layer of embryonal cells at the lobar surface, hyperplastic proliferation will produce a thick “rind” of abnormal tissue at the renal surface. Ovoid and lenticular masses result from hyperplasia of NRs that originally had these shapes. An irregular-shaped, multinodular appearance will result if only some of the cells are capable of proliferation. In contrast, WT, a neoplasm presumably arising from a single cell, tends to form spherical masses. The second important feature distinguishing actively hyperplastic NRs from WT is the usual absence of a pseudocapsule at the interface between hyperplastic NRs and the renal parenchyma.

• 4.

  Neoplastic induction is assumed to represent a clonal event originating in single cells of a rest, resulting in WT or benign adenomas. As mentioned previously rapidly growing tumors originating at a single point (or cell) will tend to grow equally in all directions, forming spherical, expansile nodules with compressed rest remnants often present at the periphery.

• 5.

  Very rarely, anaplasia may develop in nephrogenic rests.

An individual rest commonly progresses through several of these processes sequentially. For example, an incipient or dormant rest may undergo hyperplasia, followed by phases of growth arrest and maturation. This will result in a large but inactive-appearing lesion. Ultimately, one or more cells within the regressing rest may be induced to form a WT.

ILNRs are most often found at the tumor-kidney interface, where they can be misinterpreted as infiltrating tumor cells or effaced by tumor compression. A helpful feature distinguishing ILNRs at the edge of a WT is the poorly defined, irregular outer border of the ILNR, which contrasts with the sharp, pushing interface between the WT and the rest within which it arose. Also ILNRs are usually less cellular than the adjacent WT that they surround.

The presence of NRs in a kidney removed for WT is correlated with an increased risk for subsequent WT formation in the remaining kidney. The type of rest and the age of the patient modify this risk. When a carefully sampled kidney is free of rests, the risk of contralateral WT is extremely low. The possibility of subsequent WT developing in the remaining kidney should be considered in planning the follow-up of patients whose nephrectomy specimen reveals the presence of NRs in addition to WT.

Differential Diagnosis of Wilms Tumor

Gross Appearance

Clear cell sarcoma of the kidney (CCSK) is always unicentric, with a distinct tumor-kidney junction. Tumors are usually relatively large, with a mean specimen diameter of approximately 11 cm. The cut surface is often glistening and gelatinous. Cysts are almost always present and may be so prominent as to suggest cystic nephroma on gross examination or imaging studies.

Microscopic Appearance

Under low magnification, most CCSKs appear monomorphous, without the prominent lobulation usually seen in WT. CCSK usually has a scalloped border that appears fairly sharp under low power. Under higher magnification, the border appears less sharply defined because of the penetration of neoplastic cells a short distance into the surrounding kidney or the tumor capsule. This growth pattern tends to surround and isolate individual single nephrons, which is rarely if ever seen with WT. The entrapped tubules are usually confined to the peripheral 2 to 3 cm of a CCSK. Their epithelium commonly shows embryonal metaplastic changes similar to those entrapped in congenital mesoblastic nephroma, and the resultant basophilic epithelium creates confusion with WT. Dilation of these entrapped tubules produces intratumoral cysts that may mimic cystic nephroma. CCSK may show a wide variety of morphologic patterns, described in the subsequent sections.

Classic Pattern.

The hallmark of the classic pattern is an evenly distributed network of vascular septa, which has a branching, “chicken-wire” pattern similar to that seen in myxoid liposarcoma or oligodendroglioma. These fibrovascular septa subdivide the tumor into a conspicuous pattern of cords and nests, averaging six to ten cells in width, composed of polygonal cells that usually lack distinct cytoplasmic borders. Cells within the cords are less densely packed than those of blastemal WT, and overlapping nuclei are less frequent. Nuclear chromatin is usually finely granular, with inconspicuous nucleoli ( Fig. 55-4 ). In well-fixed specimens, the fine nuclear chromatin pattern is the most helpful clue to the diagnosis. However, it is influenced markedly by the timing and type of fixation. Mitotic figures are variable in number but are usually less numerous than those in WT. The cytoplasm usually lacks distinct borders and is surrounded by extracellular mucopolysaccharides, which creates the illusion of clear cytoplasm.

CCSK is easily confused with other neoplasms because the classic pattern is often modified, presenting alterations that mimic other neoplasms to a sometimes striking degree. Fortunately the classic pattern of CCSK predominates in most specimens and is present at least focally in more than 90% of tumors. However the pathologist who is unaware of these variant patterns is likely to diagnose CCSK as another neoplasm, with different therapeutic and prognostic implications. These variant patterns are described in the subsequent sections.

Ultrastructure, Immunohistochemistry, and Cytogenetics

Ultrastructural studies yield few clues as to the putative cell of origin of CCSK. The tumor cells are characterized by a high nuclear-to-cytoplasmic ratio, with nuclear shapes that are more irregular and variable than would be expected from light microscopy. The cytoplasm is usually tenuous, with elongated, irregular processes surrounding abundant intercellular matrix. This latter feature is responsible for the vacuoles often seen with the light microscope. The cytoplasm tends to be poor in organelles. Immunohistochemistry has afforded little new insight into the histogenesis of CCSK, except to exclude various potential lines of differentiation for this enigmatic neoplasm. Vimentin is positive in nearly all specimens and BCL2 in some, but other markers are consistently negative. These include stains for epithelial markers (cytokeratins and epithelial membrane antigen [EMA]), neural markers (S-100 protein), neuroendocrine markers (chromogranin, synaptophysin), muscle markers (desmin), CD34, CD117 (c-kit), and CD99 (MIC2). A subset of CCSK harbor a t(10;17)(q22;p13) chromosome translocation, resulting in a YWHAE-FAM22 gene fusion.

Differential Diagnosis of Clear Cell Sarcoma of the Kidney

The distinction of CCSK from other renal neoplasms can be extremely difficult, even for those with extensive experience in pediatric renal neoplasm pathology. The distinction of CCSK from rhabdoid tumor of the kidney is covered in the section on the latter. The major differential diagnostic concerns are discussed in the text that follows.