Epidemiology

• Majority in young children

median age at presentation 3–5 years

• Most unilateral and unicentric

synchronous tumors in a single kidney reported

bilateral lesions present in about 5%.

• Patients treated for unilateral Wilms’ tumor at increased risk of development of subsequent Wilms’ tumor

many associated with nephrogenic rests in the residual kidney (see nephrogenic rest section)

• Almost all nephroblastomas arise within the kidney but rare cases reported at extrarenal sites

most commonly perirenal, inguinal or gonadal regions

– presumably as a consequence of residual nephrogenic remnants at these sites.

Genetics

• Numerous additional candidate genes now suggested

at present, genetic studies are not used in routine clinical practice for the diagnosis or prognostication of Wilms’ tumors.

Clinical features

• Vast majority present with abdominal mass

usually detected incidentally by parents or carers

• Other symptoms and signs may occur including:

abdominal pain

hematuria

hypertension

Specific issues of specimen handling

• Most important factors being:

documentation of capsular invasion

hilar and sinus involvement

adequate sampling of tumor

Macroscopic features (Figs 1.1–1.7)

• At nephrectomy most are solitary, round masses, well-demarcated from the adjacent uninvolved kidney

fibrous pseudocapsule

• 5% multicentric

(>90% of these associated with nephrogenic rests; Breslow et al 2006)

• Macroscopic appearance on sectioning significantly influenced by preceding management

cases which have undergone chemotherapy may show a range of treatment-related changes, the extent of which may be important for risk stratification (see below)

• Postchemotherapy specimens may show significant areas of necrosis or hemorrhage

extent of which should be estimated for appropriate postchemotherapy response sub-classification to be carried out

Fig. 1.1

Fig. 1.2

Fig. 1.3

Fig. 1.4

Fig. 1.5

Figs 1.1–1.6 Macroscopic photographs of postchemotherapy nephroblastomas showing tumor which is well-demarcated from the normal renal parenchyma and with varying degrees of chemotherapy-associated changes such as necrosis, hemorrhage and cystic change. The specimens have been inked prior to sectioning.

Fig 1.7 Macroscopic photograph of postchemotherapy nephroblastoma showing a polypoid extension of tumor which has been extracted from the renal vein.

Histopathological features

• Classical histopathological features of a triphasic Wilms’ tumor include:

epithelial

stromal

blastemal elements

• Within an individual tumor, an enormously wide spectrum of histopathological features may be identified

may occasionally cause particular difficulty in interpretation when examining a needle core biopsy in which only a small, possibly unrepresentative, field of tumor is present (Figs 1.8–1.12)

• Usually, the components resemble a variety of stages of nephrogenesis

occasionally stromal components may be present which are not normally encountered in the kidney

– striated muscle and cartilage

term teratoid Wilms’ tumor has been sometimes used.

Fig. 1.8

Fig. 1.9

Figs 1.8–1.10 Photomicrographs of percutaneous needle core biopsies of pre-chemotherapy nephroblastomas demonstrating varying proportions of stromal, epithelial and blastemal elements.

Fig. 1.11

Figs 1.11–1.12 Photomicrographs of a ‘gelfoam’ granuloma in a nephroblastoma. Such features may be encountered in nephrectomy specimens which have previously undergone percutaneous needle biopsy, foreign-material having been inserted via the needle tract to reduce bleeding.

Fig. 1.13

Figs 1.13–1.14 Photomicrographs of nephroblastomas showing the classical architectural and morphological mixture of elements.

Epithelial component (Figs 1.15–1.18)

• Majority of Wilms’ tumors show some areas of obvious morphologic epithelial differentiation

• Tubular structures, rosette-like areas, and glomeruloid structures

• Note: rosette-like structures may be morphologically similar to neuroblastoma in some cases

• Occasionally, heterologous epithelium may also be seen

such as mucinous or squamous

Fig. 1.15

Figs 1.15–1.16 Photomicrographs of nephroblastomas showing epithelial elements manifest as well-formed tubular structures.

Fig 1.17 Photomicrograph of a nephroblastoma showing epithelial elements which merge imperceptibly with blastemal elements.

Fig 1.18 Photomicrograph of a nephroblastoma showing an area of squamous differentiation.

Blastemal component (Figs 1.19–1.21)

• Represents relatively poorly-differentiated mesenchymal tissue normally seen early in renal development

• Blastemal areas have many of the features of a classical embryonal ‘small round blue cell tumor’

round to ovoid cells

high nuclear-to-cytoplasmic ratio

closely packed nuclei

nuclear overlapping

mitoses

chromatin is often finely dispersed

focally the cells may appear dyscohesive

• Several architectural patterns reported, none of which appear to have any prognostic significance, but their recognition may aid diagnosis, particularly in cases in which blastema is the only, or predominant, component

these include

– diffuse blastemal (which is associated with characteristic invasive growth)

– nodular blastemal

– serpentine blastemal

– basaloid blastemal (rare)

Fig. 1.19

Figs 1.19–1.20 Photomicrographs of nephroblastomas showing blastemal areas admixed with other elements.

Fig 1.21 Photomicrograph of a post-chemotherapy nephroblastoma showing sheets of blastemal tissue with focally degenerative change (upper right).

Stromal component (Figs 1.22–1.25)

• Stromal component may vary widely from areas of stellate cells within a myxoid background to spindle cells recapitulating primitive mesenchyme

• Smooth and striated muscle are the most common differentiated stromal cell types

• Occasionally, a wide range of other stromal components may be present including fat, cartilage, osteoid and even glial tissues

Fig. 1.22

Fig. 1.23

Figs 1.22–1.24 Photomicrographs of nephroblastomas showing predominant stromal differentiation admixed with other elements.

Fig 1.25 Photomicrograph of a nephroblastoma showing marked rhabdomyomatous stromal differentiation.

Post-chemotherapy features (Figs 1.26–1.30)

• Characteristic features described above most commonly seen in prechemotherapy specimens, either needle biopsies at diagnosis, or tumors treated with primary nephrectomy

• In cases in which previous chemotherapy has been carried out prior to nephrectomy, a similar range of components may be identified but their significance may be different and there may be superimposed chemotherapy-associated changes such as:

necrosis

fibrosis

foamy and hemosiderin-laden macrophages

• During chemotherapy, rapidly dividing cells, such as those of the blastemal or primitive epithelial components, tend to respond, whereas the stromal elements will not

tumors with significant stromal differentiation may not reduce much in size during chemotherapy

stromal components may appear more prominent in a postchemotherapy specimen

• Histological assessment of tumor responsiveness to chemotherapy is of additional prognostic importance

for example, a tumor which remains predominantly viable following chemotherapy, in which the main component is blastema, is associated with an adverse prognosis and therefore is considered a high risk tumor

• The SIOP classification specifically includes extent of postchemotherapy changes for assigning tumor risk type

Fig. 1.26

Fig. 1.27

Fig. 1.28

Figs 1.26–1.29 Photomicrographs of post-chemotherapy nephroblastomas showing areas of marked regressive change including frank necrosis, hemorrhage, fibroblast proliferation and accumulation of hemosiderin-laden and foamy macrophages.

Fig 1.30 Photomicrograph of post-chemotherapy nephroblastoma showing marked regressive change but with residual areas of blastema; it is important to histologically sample even areas which appear regressive on macroscopic examination.

Unfavorable histology Wilms’ tumor (anaplasia) (Figs 1.31–1.34)

• A range of histological features may be associated with an adverse prognosis

encompassed by the term unfavorable histology

• In early classifications, (and still highlighted in the current COG/SIOP risk classifications), other entities representing non-Wilms’ malignant renal tumors of infancy were also considered in the high risk group

these are now best classified as distinct entities

• Very rarely, a frankly malignant component develops within a pre-existing Wilms’ tumor

high-grade sarcoma or carcinoma

– recognized by an independent growth pattern

associated with a poor prognosis, but are uncommon

• The term ‘unfavorable histology Wilms’ tumor’ most commonly used to represent the presence of anaplasia within an otherwise classical Wilms’ tumor, or a tumor in which the response to pre-nephrectomy chemotherapy has been poor with extensive residual blastema (SIOP postchemotherapy classification)

• ‘Nuclear anaplasia’ in the context of Wilms’ tumor has very specific criteria required for its definition

nuclear hyperchromasia

nuclear enlargement

– affected nuclei are at least three times the size of adjacent non-anaplastic nuclei

abnormal, multipolar mitoses

• Using such criteria, anaplasia is present in approximately 5–10% of Wilms’ tumors

more commonly in those diagnosed in later childhood and in black patients (Dome et al 2006)

• ‘Nuclear unrest’ represents presence of cytologically abnormal features in Wilms’ tumor but insufficient for ‘anaplasia’

usually showing enlargement and hyperchromasia without abnormal mitoses.

appear to behave intermediately between favorable and anaplastic types (Hill et al 2003)

• Anaplasia may either be focal or diffuse

focal:

– one, or a few, well-circumscribed, localized regions of anaplasia within the primary tumor

– completely excised

– majority of tumor containing no significant nuclear atypia

diffuse:

– anaplasia occurring in multiple fields or outside the primary tumor

• Diffuse anaplasia is associated with poor response to chemotherapy

major clinical significance when present in tumors which are potentially incompletely excised

• Focal anaplasia or anaplasia in stage I cases initially thought to carry no adverse prognostic significance

now being re-evaluated since prognosis appears worse with anaplasia even in stage I cases, and any anaplasia may be of importance (Dome et al 2006)

• Anaplasia identified as adverse prognostic factor but

recently suggested that there may be a gene expression signature for relapse of primary Wilms’ tumors independent of anaplasia (Li et al 2005a)

transcription profiling indicates that a cluster of genes separates anaplastic from non-anaplastic Wilms’ tumor (Li et al 2005b)

Fig. 1.31

Fig. 1.32

Fig. 1.33

Figs 1.31–1.34 Photomicrographs of nephroblastomas with diffuse anaplasia showing areas with marked nuclear pleomorphism, enlargement, hyperchromasia and abnormal, multipolar mitotic figures.

Special stains

• Tinctorial stains of no particular value in Wilms’ tumor

may be useful for assessing lymphovascular invasion, as with any other malignancy

Immunohistochemical staining

• However, immunohistochemical staining is often extremely useful in the diagnosis of Wilms’ tumor from a needle core biopsy (Figs 1.35, 1.36)

core biopsy may simply demonstrate ‘small round blue cell tumor’, which could represent the blastema of Wilms’ tumor or morphologically, several other embryonal tumors of infancy and childhood

• Most useful immunohistochemical marker is WT1

blastemal and primitive epithelial areas in Wilms’ tumor show diffuse nuclear expression

– note that areas of stromal differentiation, and well-differentiated epithelial structures, may not express nuclear WT1

Fig. 1.35

Figs 1.35–1.36 Photomicrographs of percutaneous needle core biopsies of pre-chemotherapy nephroblastomas demonstrating a nodular monomorphic population of tumor cells which strongly express CD56 (Fig 1.35) and nuclear WT1 (Fig 1.36).

Classification and staging

See Tables 1.2–1.4

Table 1.2 SIOP Classification (Vujanic et al 2002)

If necrosis and regressive change comprises more than two-thirds of the tumor mass it is a regressive type.

If regressive change / necrosis comprises less than two-thirds of the tumor mass a predominant histological component should be looked for and the tumor subclassified accordingly.

For a component to be regarded as dominant, more than two-thirds of the viable tumor must be composed of the subtype.

If >10% and <66% of the viable tumor is blastema, mixed type regardless of ‘dominant’ component.

To fulfill the diagnosis for completely necrotic subtype there must be no viable tumor present on gross and microscopic examination of multiple blocks from different areas of the tumor sampled at least one block per centimeter of tumor largest diameter, in combination with the presence of regressive and necrotic changes caused by chemotherapy.

Table 1.3 Staging system: SIOP

Table 1.4 Staging system: COG

Special diagnostic investigations

Differential diagnoses and pitfalls

• Main practical difficulties in the initial diagnosis of a Wilms’ tumor are in the interpretation of a needle core biopsy containing a ‘small round cell tumor’

major differential diagnoses are

– blastematous component of Wilms’ tumor versus other small round cell tumors of childhood especially

· neuroblastoma

· synovial sarcoma

· primitive neuroectodermal tumor

· clear cell sarcoma of the kidney

· renal rhabdoid tumor

· renal lymphoma

in most, these can readily be distinguished using a range of immunohistochemical markers

note: if immunostaining is to be used for diagnostic purposes of needle core biopsies, it should be noted that many other embryonal tumors may express cytoplasmic WT1 (depending on the antibody used), and caution should be taken to only interpret nuclear staining as suggestive of Wilms’ tumor

note also that both desmoplastic small round cell tumor and some myeloid leukemias may also strongly express nuclear WT1 depending on the antibody used

• Other specific diagnostic pitfalls include the assessment of renal capsular invasion

in particular the distinction between the true fibrous pseudocapsule of the tumor, the renal capsule and the presence of an inflammatory pseudocapsule

– technique of ‘horizontal analysis’ of the capsule

· capsular layers are followed laterally to determine the deepest level of tumor penetration

• Since the presence of tumor at the margins is of considerable staging importance, it is also important to minimize artefactual displacement of tumor cells during handling

recommended that the tumor be inked prior to sections being taken

• A further specific issue which often causes difficulty is the assessment of the renal vein margin in cases of intravascular extension since following transection of the vein during surgery, the vein margin may significantly retract leaving tumor protruding into the lumen (Figs 1.37, 1.38)

in such cases clinicopathological correlation is of importance and in histological sections of the vein margin tumor must be seen invading the vascular wall as opposed to simply surrounding tumor within the lumen, to be classified as involved

• Assessment of lymph node metastasis may occasionally be difficult since sometimes only small microscopic, clumps of tumor cells may be present in the subcapsular region (Fig 1.39)

occasionally there may also be marked accumulation of Tamm–Horsfall protein within the subcapsular sinus (Fig 1.40)

– may also be associated with displaced renal tubular cells

immunohistochemical staining may be useful in this regard

Fig 1.37 Photomicrograph showing involvement of hilar renal vein branch by postchemotherapy nephroblastoma.

Fig 1.38 Photomicrograph of tumor surgically extracted from the inferior vena cava in a case of Wilms’ tumor showing residual viable tumor including islands of blastema.

Fig 1.39 Photomicrograph of a hilar lymph node from a patient with Wilms’ tumor showing microscopic subcapsular tumor deposits, confirmed on WT1 immunostaining (inset).

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