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.

Wilms tumor, favorable histology, triphasic pattern.

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 ).

Wilms tumor, favorable histology, diffuse blastemal pattern.

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.

Wilms tumor, anaplastic.

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.

Clear cell sarcoma of the kidney.

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.

Gross Appearance

CMN arises unicentrically and usually appears to have arisen deep within the medial parenchyma, near the renal sinus. The renal sinus and adjacent structures on the medial side of the kidney are major sites of extrarenal spread of CMN. Surgeons and pathologists must pay particular attention to the medial margin of the CMN resection specimen. However because of the predominance of freely mobile fat in this location and retraction artifact, the medial specimen margin is notoriously difficult to evaluate, and it is rarely possible to be certain that it is free of involvement by CMN.

The appearance of the sectioned surface of CMN is variable and depends on the subtype. Classic CMNs have a tough, whorled appearance resembling that of leiomyoma, but cellular CMNs may be soft, friable tumors. Hemorrhage, necrosis, and cyst formation are present to some degree in a majority of cellular CMNs.

Microscopic Appearance

CMN is a low-grade fibroblastic sarcoma of the infantile kidney. The classic type of CMN has a fibrous, whorled gross appearance. Morphologically, classic CMN is identical to infantile fibromatosis; it is composed of bland fibroblastic or myofibroblastic cells, arranged in fascicles that dissect into the native kidney ( Fig. 55-5 ). Mitoses are usually rare, and necrosis is absent. The leading edge of the tumor characteristically induces angiomatous vascular proliferation where it abuts perirenal fat. Entrapped renal tubules may acquire a primitive appearance (embryonal metaplasia), which may cause confusion with true neoplastic tubular differentiation that would suggest a diagnosis of biphasic stromal-epithelial WT. In contrast, the cellular variant of CMN typically has a softer, more fleshy and hemorrhagic appearance with necrosis and cystification. Microscopically, cellular CMN is identical to infantile fibrosarcoma (IFS). Compared with the classic variant, cellular CMNs more often have a “pushing” border, demonstrate sheetlike growth patterns, are less often fascicular, are more cellular, and have a higher mitotic rate ( Fig. 55-6 ). Tumor cells may be polygonal with well-demarcated pink cytoplasm and nuclei with vesicular chromatin and prominent nucleoli; this raises the differential diagnosis of rhabdoid tumor of the kidney. Alternatively the tumor cells may be thinner, primitive, and spindled, yielding a more embryonal “blue cell” appearance. Mixed CMNs have areas identical to both cellular and classic CMN in varied proportions within the same tumor.

Congenital mesoblastic nephroma, classic type.

Congenital mesoblastic nephroma, cellular type.

Immunohistochemistry and Ultrastructure

Immunohistochemistry is of limited value in the diagnosis of CMN. The cells of CMN label in a fashion consistent with fibroblasts or myofibroblasts. Whereas actin may be focally positive, desmin and CD34 are typically negative (P. Argani, unpublished observations). INI1 protein is retained. Ultrastructural studies also reveal features consistent with fibroblasts or myofibroblasts. Most CMN cells show abundant rough endoplasmic reticulum with branching and anastamosing profiles, and primitive cell junctions are often found.

Differential Diagnosis of Congenital Mesoblastic Nephroma

The differential diagnosis for CMN includes stromal-predominant WT, CCSK, metanephric stromal tumor (MST) and malignant rhabdoid tumor (MRT). These distinctions are crucial because most children with CMN do not require adjuvant chemotherapy, whereas those with WT, CCSK, and MRT are treated on specific chemotherapy protocols. Features that distinguish CCSK and MRT from CMN are covered in the sections on CCSK and MRT, respectively. The features that distinguish CMN from WT and MST are expanded on in the subsequent sections.

Gross Appearance

Most MRTs are relatively small because metastasis occurs early in the evolution of the neoplasm. On gross examination MRTs are typically fleshy or hemorrhagic neoplasms, with ill-defined borders and frequent satellite nodules that reflect the tumor’s highly invasive nature.

Microscopic Appearance

MRT was so named because of the resemblance of the tumor cells to rhabdomyoblasts. However this highly lethal infantile neoplasm does not demonstrate muscle differentiation. Microscopically these neoplasms typically engulf native renal elements at their periphery and demonstrate extensive vascular invasion. MRT classically consists of sheets of monotonous cells featuring a characteristic cytologic triad: vesicular chromatin, prominent nucleoli, and hyaline cytoplasmic inclusions ( Fig. 55-7 ). These features are variably well developed within a given tumor, which means that it may be necessary to examine multiple microscopic fields from many sections to find them.

Malignant rhabdoid tumor of the kidney.

Ultrastructure and Immunohistochemistry

Ultrastructurally the cytoplasmic inclusions correspond to whorled intermediate filaments. The whorled filaments may trap antibodies used for immunohistochemistry, yielding a nonspecific polyphenotypic pattern. With this caveat, strong vimentin and focal EMA labeling are characteristic immunohistochemical findings. Recently, an immunohistochemical assay for INI1 protein has become available. Loss of INI1 protein expression reflects INI1 genetic status and, within the kidney, is a sensitive and nearly specific marker for MRT.

Differential Diagnosis of Rhabdoid Tumor of the Kidney

The diagnosis of MRT is often challenging because a wide variety of renal and extrarenal tumors of adult and children may feature fully developed “rhabdoid” cytology, at least focally. In the pediatric kidney these include cellular CMN (of the plump cell type), CCSK, blastemal WT, PNET, renal medullary carcinoma, and rhabdomyosarcoma. In general, thorough sampling of such tumors is most helpful, insofar as it typically reveals specific differentiation that excludes MRT. Additionally, the age of the patient is very helpful because MRT is not seen outside of early childhood. Finally, in the kidney loss of INI1 protein expression by immunohistochemistry is highly specific for MRT or renal medullary carcinoma. Several specific differential diagnoses are covered in the subsequent sections.

Xp11.2 Translocation Renal Cell Carcinomas

RCCs with chromosome translocations involving Xp11.2 and resulting gene fusions involving the TFE3 transcription factor gene were officially recognized in the 2004 World Health Organization Renal Tumor Classification. Although this subtype of RCC is relatively uncommon on a percentage basis in adults, it most likely accounts for the majority of pediatric RCCs. One distinctive subtype bears a t(X;17)(p11;q25), which results in the identical ASPL-TFE3 gene fusion, as was initially identified in alveolar soft part sarcoma (ASPS), and has been designated the ASPL-TFE3 RCC. Other subtypes are listed in Table 55-3 .

Xp11.2 translocation RCCs closely resemble conventional (clear cell) renal carcinomas on gross examination, usually being tan-yellow and often necrotic and hemorrhagic. A papillary carcinoma composed of clear cells is the most distinctive histopathologic appearance ( Fig. 55-8 ), because this combination is uncommon in other defined types of renal carcinomas. However the Xp11.2-translocation RCCs often have nested architecture and often contain cells with granular eosinophilic cytoplasm. The histologies of Xp11-translocation RCC associated with different TFE3 gene fusions differ. The ASPL-TFE3 RCCs feature cells with voluminous, clear to eosinophilic cytoplasm, discrete cell borders, vesicular nuclear chromatin, and prominent nucleoli. In contrast, the PRCC-TFE3 RCCs, characterized by a t(X;1)(p11.2; q21), typically have less abundant cytoplasm; fewer psammoma bodies; fewer hyaline nodules; and a more nested, compact architecture.

Xp11.2 translocation renal cell carcinoma.

Renal carcinomas with Xp11.2-associated translocations characteristically underexpress epithelial immunohistochemical markers such as cytokeratin and epithelial membrane antigen. Only approximately one half of cases will be positive with these markers, and the labeling is often focal. Vimentin immunoreactivity is also often focal compared with that of the adjacent blood vessels; this also differs from conventional RCCs, which are diffusely positive. Rare Xp11.2-translocation carcinomas, especially ones with variant gene fusions such as PSF-TFE3 and CLTC-TFE3 , express melanocytic markers HMB45 and Melan A, creating confusion with epithelioid angiomyolipoma. Cathepsin K, a serine protease normally expressed in osteoclasts, is expressed in approximately 50% of translocation RCC but no other subtype of RCC. The most distinctive immunohistochemical feature of these neoplasms is nuclear labeling for TFE3 protein using an antibody to the C-terminal portion of TFE3, which is retained in the gene fusions. Nuclear labeling for TFE3 is a common feature of all Xp11.2-translocation RCC and ASPS but does not occur in other RCCs ( Fig. 55-9 ). Because native TFE3 is known to be ubiquitously expressed but is not detectable in normal tissues by immunohistochemistry, it is postulated that the different TFE3 gene fusions consistently lead to overexpression of the fusion protein relative to native TFE3, such that the protein becomes detectable by this assay. However TFE3 immunohistochemistry is difficult to optimize in the setting of variable fixation, and a break-apart fluorescence in situ hybridization (FISH) assay for TFE3 gene rearrangements is a more reliable assay in formalin-fixed, paraffin-embedded tissue.

Xp11.2 translocation renal cell carcinoma, TFE3 immunohistochemistry.

When analyzed by electron microscopy, Xp11.2-associated carcinomas feature cell junctions, microvilli, intracytoplasmic fat, and glycogen and thereby most closely resemble conventional renal carcinomas. However a subset of cases demonstrates distinctive ultrastructural features. Most of the ASPL-TFE3 RCCs contain membrane-bound cytoplasmic granules, and a few have membrane-bound rhomboidal crystals that are identical to those seen in soft tissue ASPS. Some PRCC-TFE3 RCCs have had distinctive intracisternal microtubules similar to those seen in malignant melanoma and extraskeletal myxoid chondrosarcoma.

t(6;11)(p21;q12) Renal Cell Carcinomas

Another distinctive type of RCC bears a t(6;11)(p21;q12). The distinctive clinicopathologic features of these neoplasms were not described until 2001. On microscopic examination these neoplasms usually feature nests and tubules of polygonal epithelioid cells, separated by thin capillaries. Some cases have had papillary formations. The majority of the tumor cells have abundant clear to granular eosinophilic cytoplasm, well-defined cell borders, and round nuclei with small nucleoli. However a second population of smaller epithelioid cells is also characteristic, typically (but not always) clustered around nodules of hyaline basement membrane material within larger acini ( Fig. 55-10 ). The cases examined have generally been negative for cytokeratins by immunohistochemistry, but almost all have labeled at least focally for HMB45, Melan A, and Cathepsin K, again creating confusion with epithelioid angiomyolipoma.

Renal cell carcinoma with t(6;11) (p12;q12) translocation.

The t(6;11)(p21;q12) has been shown to result in a fusion of the intronless, untranslated Alpha gene with TFEB, a gene belonging to the same transcription factor family as TFE3 . The consequence of the Alpha-TFEB fusion is dysregulated expression of the normal full-length TFEB protein. Along these lines, the t(6;11) RCCs (also known as Alpha-TFEB RCCs) demonstrate specific nuclear labeling for TFEB protein by immunohistochemistry (IHC), whereas other neoplasms and normal tissues do not ( Fig. 55-11 ). Hence nuclear labeling for TFEB is a sensitive and specific diagnostic marker for this neoplasm with a TFEB gene fusion, just as nuclear labelling for TFE3 is a sensitive and specific marker for neoplasms bearing TFE3 gene fusions. A break-apart FISH assay for TFEB gene rearrangements has recently been developed for formalin-fixed, paraffin-embedded tissue and is proving to be more sensitive than TFEB IHC assay.

Renal cell carcinoma with t(6;11) (p12:q12) translocation, transcription factor EB immunohistochemistry.

Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) was first described in 1995 by Davis and colleagues as “the seventh sickle cell nephropathy.” These tumors characteristically affect young patients (mean age, 22 years) with sickle cell trait. Tumors are typically centered in the renal medulla but demonstrate an aggressively infiltrative growth pattern with frequent vascular permeation. The tumor cells feature vesicular chromatin and prominent nucleoli, frequently associated with hyaline intracytoplasmic inclusions, therefore imparting a rhabdoid cytologic appearance. The tumor cells of RMC demonstrate diffuse (sheetlike), cribriform, gland-forming, microcystic, or reticular growth patterns, the latter two simulating yolk-sac tumor ( Fig. 55-12 ). The stroma is typically desmoplastic and infiltrated by neutrophils, and close examination of extravasated red blood cells may reveal sickling. However, hemoglobin electrophorosis is more reliable than the latter for determining that the patient has sickle cell trait. These tumors frequently present at high stage and are highly lethal; Davis and colleagues reported a mean survival of only 15 weeks. Given their medullary epicenter and high-grade cytology, RMCs are considered by some to be variants of collecting duct carcinoma, although the latter entity is a notoriously elusive one to define. As noted previously, RMCs consistently show loss of expression of INI-1 protein by IHC, similar to RTK.

Renal medullary carcinoma.

Oncocytic Renal Carcinomas in Neuroblastoma Patients

Meideros and coworkers have described oncocytic renal carcinomas arising in children who had previously had neuroblastoma. The genetic alterations identified in these lesions did not match those of known renal carcinomas, suggesting that these are another distinctive entity.

WT1

WT1 was the first gene found to be specifically mutated in WT. The gene was originally identified via study of patients with the WAGR syndrome. Children with WAGR suffer from the constellation of W T, a niridia, g enitourinary abnormalities, and mental r etardation. Chromosomal analysis of these patients revealed heterozygous constitutional deletions at 11p13. Subsequent investigation of the genes contained within these deletions identified disruption of the PAX6 gene as the basis of aniridia and WT1 as the key tumor suppressor. The remaining allele of WT1 is mutated in the WTs from these patients.

WT1 encodes an approximately 45-kd DNA-binding protein that contains domains rich in glutamine and proline in the amino terminus and four zinc fingers in the carboxy terminus, collectively suggesting that it acts as a transcription factor. The WT1 gene is quite complex insofar as it encodes numerous distinct isoforms and contains an evolutionarily conserved cryptic splice site that can result in the insertion of three amino acids, lysine, threonine, and serine (KTS), between zinc fingers 3 and 4. Notably distinct functions have been identified for the different KTS isoforms. Patients with Frasier syndrome, characterized by male pseudohermaphroditism, progressive glomerulopathy, and an increased risk of WT, have a congenital donor splice-site mutation in WT1 that results in loss of the +KTS isoform. Furthermore mice that express only the +KTS or only the −KTS isoform have distinct phenotypes.

Congenital point mutations in WT1 are also the basis of Denys-Drash syndrome. Patients with this syndrome suffer from renal failure, pseudohermaphroditism, and a susceptibility to WT. Denys-Drash syndrome is caused by missense mutations in WT1 that disrupt zinc finger binding to DNA. The phenotype of patients with Denys-Drash is quite severe, and evidence suggests that these mutations may lead to a dominant-negative protein that impairs function of the normal protein encoded by the remaining allele. Nonetheless the remaining WT1 allele is mutated in the WTs that arise in these patients, suggesting that mutation of both alleles is required for tumor formation. Notably whereas mutations in WT1 are the basis of several syndromes that predispose to the formation of WT, WT1 is mutated in only 10% to 20% of sporadic tumors. Mouse models have provided insight into the contributions of WT1 to development and tumor suppression. WT1 is expressed at high levels in the developing kidney, gonads, spleen, and mesothelium and at lower levels in several other tissues. Mice deficient for WT1 die midgestation with abnormalities of the metanephric blastema, gonads, mesothelium, heart, and lungs. Cells from the metanephric blastema in these mice undergo apoptosis, and consequently the metanephric kidney never develops. Based on these data it has been postulated that the WT1 protein regulates gene expression pathways required for morphogenesis of the kidney, and that its disruption results in aberrant stimulation of tissue-specific growth. This role in differentiation may also explain why WT is largely a disease of early childhood insofar as kidney morphogenesis is initiated in utero and is completed in early postnatal life. Indeed the level of WT1 plummets within a few weeks after birth in mice. Whereas WT1 ^−/− mice are not viable, WT1 ^+/− mice live but do not develop WTs. This differs from the human condition in which individuals with germline WT1 deletions or mutations have a greatly increased risk for developing WT compared with the general population.

β-catenin (CTNNB1)

The Wnt signaling pathway regulates the cellular processes of proliferation, differentiation, motility, and survival. Central to the pathway is the transcriptional activator β-catenin, which is actively degraded in the absence of Wnt signaling. Activating mutations in the β-catenin (CTNNB1) gene occur in approximately 15% of WTs. Interestingly mutations in β-catenin occur predominantly in tumors in which WT1 is also mutated, suggesting that these two events cooperate in the genesis of WT. In the developing kidney Wnt4 is an inducer of the mesenchymal to epithelial transition that underlies normal nephron development; disruption of normal renal development may be the means by which β-catenin mutation contributes to the formation of WT.

WTX (AMER1/FAM123B)

WTX was discovered by an array comparative genomic hybridization screen that identified deletions of the Xq11.1 locus in male patients with WT. Further investigation found deletions and mutations in girls. Intriguingly WTX is inactivated by a single hit affecting either the sole WTX copy in male subjects or the copy located on the active X chromosome in female subjects. According to the initial report, WTX was deleted or mutated in approximately one third of WTs, although other groups have reported a lower mutation frequency. Germline WTX mutations have been observed in individuals with osteopathia striata congenita with cranial sclerosis, a rare slerosing bone dyspasia. Individuals with osteopathia striata congenita with cranial sclerosis do not have increased risk for WT or other cancers, but NRs have been observed in one individual with a germline WTX mutation.

WTX is alternatively spliced to encode two isoforms of a protein with disparate functions. The short isoform of the protein is nuclear and forms a complex with β-catenin, AXIN1, APC, and β-TrCP2, ultimately promoting ubiquitination and degradation of β-catenin, thereby acting as a negative regulator of the WNT signaling pathway. The full-length WTX protein binds to the adenomatous polyposis coli protein and regulates its distribution between microtubules and the plasma membrane. WTX also interacts with WT1 protein and enhances its function as a transcriptional activator. It was recently shown to bind p53 and modulate p53 function through its activator CBP/p300.

Although WT1 and β-catenin mutations are highly concordant, there is no clear association between WT1 and WTX mutations. This suggests that WTX and β-catenin mutations are not functionally equivalent even though both proteins reside within the WNT pathway.

IGF2

Cytogenetic analyses have long suggested the presence of an additional WT gene at 11p15 distinct from the WT1 locus at 11p13. Loss of heterozygosity (LOH) at 11p15 occurs in some cases of sporadic WT. Additionally, this locus is linked to Beckwith-Wiedemann syndrome (BWS), an overgrowth disorder associated with macroglossia, umbilical hernia, gigantism, neonatal hypoglycemia, and predisposition to WT and other cancers. BWS arises from alterations in several different genomically imprinted genes at the 11p15 locus. Genomic imprinting is the preferential expression of a gene from either the maternal or paternal allele. The molecular basis of genomic imprinting is epigenetic modification, most notably DNA methylation. The 11p15 locus has two imprinting domains ( Fig. 55-13 ). The telomeric domain (domain 1) includes the genes insulin-like growth factor 2 (IGF2) and H19 . IGF2 encodes a growth factor expressed at high levels in the developing kidney and WT. 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. The centromeric imprinting domain (domain 2) contains several imprinted genes, including KCNQ1 ( KvLQT1 ) , KCNQ1OT1 (LIT1 ) , and CDKN1C ( p57 ^KIP2 ). KCNQ1 encodes a subunit of a voltage-gated potassium channel that is implicated in several cardiac arrhythmia syndromes, including long-QT syndrome 1. KCNQ1OT1 encodes a noncoding RNA with antisense transcription of KCNQ1 . CDKN1C encodes a member of the cyclin-dependent kinase inhibitor family of proteins that negatively regulates cell proliferation and is a tumor suppressor. Molecular subgroups of BWS include those with (1) loss of methylation in domain 2, which is associated with decreased expression of CDKN1C (∼50%); (2) duplication of domains 1 and 2 of the paternal allele with no maternal contribution (uniparental isodisomy) (∼20%); (3) mutation of CDKN1C (∼10%); (4) gain of methylation of domain 1, resulting in increased IGF2 expression and decreased H19 expression (∼2% to 7%); 5) small duplications or chromosome rearrangements (<2%); and (5) unknown genetic etiology (∼13% to 15%). Interestingly, the Silver-Russell syndrome, associated with growth retardation, is caused by loss of methylation at domain 1 and maternal 11p15 duplication (i.e., the opposite of BWS). ^,

The Beckwith-Wiedemann syndrome locus. The chromosome 11p15.5 locus contains several imprinted genes clustered in two imprinting domains: centromeric (cen) and telomeric (tel) . Each domain has a differentially methylated region (DMR) that controls expression of surrounding genes. In normal individuals the DMR of domain 1 is methylated in the paternal allele, resulting in expression of IGF2 and silencing of H19 . In normal individuals the DMR of domain 2 is methylated in the maternal allele, resulting in expression of CDKN1C (p57) and KCNQ1 and silencing of KCNQ1OT(LIT1) . Beckwith-Wiedemann syndrome can arise from decreased methylation of domain 2, increased methylation of domain 1, duplication of the paternal 11p15 allele with no contribution of the maternal allele (uniparental isodisomy), or small deletions or rearrangements. Increased methylation of domain 1 and uniparental isodisomy carry the greatest risk of Wilms tumor.

In the past decade correlations between BWS genotypes and cancer predisposition have emerged. Uniparental isodisomy and gain of methylation at domain 1 carry the highest risk of WT. Loss of methylation at domain 2 is associated with omphalocele, macrosomia, and a distinct lack of WT, although these individuals develop other tumor types. A common thread in the patients most susceptible to WT is increased expression of IGF2 .

TP53

Constitutional mutations of the TP53 gene are responsible for Li-Fraumeni syndrome (LFS), which predisposes carriers to cancer. TP53 , one of the most commonly mutated genes in human cancer, encodes a transcription factor that is a master regulator of cell cycle arrest, apopotosis, and DNA repair in response to a variety of stimuli. Although WT is not a defining criterion for LFS, several LFS families with WT have been identified. It is important to note that TP53 mutations are associated with the anaplastic histology subtype of WT; approximately 75% of anaplastic WTs have detectable TP53 mutations, whereas TP53 mutations are uncommon in favorable histology tumors. Several lines of evidence suggest that anaplastic WT arises from the acquisition of a TP53 mutation in a favorable histology WT. First, patients with bilateral WT often have discordant histologies between contralateral tumors. Second, some WTs have favorable histologic features at diagnosis but are found to have anaplastic histology at relapse. Finally, microdissected WTs were found to have TP53 mutations restricted to areas of anaplasia within the tumor tissue.

Surgery

In the SIOP treatment protocols, patients 6 months of age or older receive chemotherapy before surgery unless there is evidence of tumor rupture, in which case they undergo immediate nephrectomy. Open or needle biopsy is not routinely performed. Infants younger than 6 months old are treated with upfront nephrectomy because non-Wilms renal tumors, such as mesoblastic nephroma or malignant rhabdoid tumor, are prevalent in this age group.

In the COG treatment protocols, all patients are considered candidates for immediate surgery, although there are several indications to give preoperative chemotherapy: (1) bilateral WT; (2) tumor thrombus in the inferior vena cava above the level of the hepatic veins; (3) tumors that invade adjacent organs such that resection of the tumor would involve resection of the other structures (except the adrenal gland); (4) tumors that, in the surgeon’s judgment, would result in significant morbidity or mortality if resected before chemotherapy; and (5) respiratory distress resulting from extensive pulmonary metastatic disease. If preoperative chemotherapy is given, it is recommended not to delay definitive surgery beyond week 12 of treatment.

A generous transabdominal, transperitoneal, or thoracoabdominal incision is recommended for adequate exposure. An increased rate of rupture and complication is associated with a midline laparotomy. Complete exploration of the abdomen should be performed, followed by a radical nephrectomy, dividing the ureter as distally as possible. Routine exploration of the contralateral kidney is not recommended if imaging is satisfactory and does not suggest a bilateral process because the chance of detecting a contralateral kidney tumor during surgery that is undetected with modern imaging techniques is less than 1%, and the outcome of these patients is excellent. An important component of WT surgery is lymph node sampling, even if the nodes appear normal. NWTS-4 showed that patients with positive lymph nodes had better outcomes than patients whose lymph nodes were not sampled, indicating that some patients who did not undergo lymph node sampling were understaged and undertreated. Another important facet of surgery is to remove the tumor en bloc, avoiding tumor spillage. Intraoperative spillage was shown to increase the risk of tumor recurrence. In a review of the first 2000 patients enrolled on COG Biology and Risk Stratification study AREN03B2, an intraoperative rupture rate of 9.7% was found in 1131 primary nephrectomies for unilateral WT. Risk factors for intraoperative spill were diameter (>12 cm) and laterality (right).

Surgical resection or biopsy of lung nodules plays an important role in the diagnosis of metastatic WT. Current COG renal tumor studies consider circular lung nodules, regardless of size, to be metastatic disease unless proven benign by biopsy. The resection of lung metastases may also provide a therapeutic benefit. In the SIOP protocols, patients whose lung nodules are resected completely do not receive pulmonary radiation therapy (XRT). The COG AREN0533 study tested a new strategy for favorable-histology WT with lung metastases. Lung nodules were assessed after 6 weeks of chemotherapy and XRT omitted for patients with a complete response. With this approach it is appropriate not to resect all lung nodules upfront to assess chemosensitivity.

Radiation Therapy

Radiation therapy is a mainstay of WT treatment. Initially used in all patients with WT, successive studies from the NWTSG and SIOP demonstrated that only patients with stage III or IV disease require radiation therapy ( Table 55-5 ). Among these patients radiation doses have been reduced over time, thereby decreasing the potential for late adverse effects.

TABLE 55-5

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