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).

Fig 1.40 Photomicrograph of a hilar lymph node from a patient with a large Wilms’ tumor showing Tamm–Horsfall protein in the subcapsular sinus.

Epidemiology

Genetics

Clinical features

• Presentation identical to other pediatric renal tumors

usually with an otherwise asymptomatic abdominal mass or abdominal pain

• 5% metastatic disease at presentation

up to 60% of these with bone metastases

Macroscopic features (Figs 1.46–1.48)

Fig. 1.46

Fig. 1.47

Figs 1.46–1.48 Macroscopic photographs of nephrectomy specimens containing clear cell sarcoma of kidney, demonstrating renal expansion by a predominantly solid tumour with a uniform cream-white cut surface.

Histopathological features (Figs 1.49–1.58)

• Classical pattern demonstrates nests (or cords) of ovoid cells separated by fibrovascular septa

cord cells may be ovoid, epithelioid or spindled with bland nuclei without prominent nucleoli

septa demonstrate marked regular branching ‘chicken wire’ pattern of capillaries

• However, many clear cell sarcomas of the kidney do not conform to this characteristic pattern and a wide variety of other patterns have been described

include myxoid, sclerosing, cellular, epithelioid, pallisaded, spindled, storiform and anaplastic variants

most cases composed of a mixture of such patterns

Fig 1.49 Photomicrograph of a needle core biopsy of a clear cell sarcoma of kidney showing a uniform appearance of apparently bland, plump, ovoid cells at low power.

Fig. 1.50

Fig. 1.51

Figs 1.50–1.52 Photomicrographs of nephrectomy specimens of clear cell sarcoma of kidney showing the absence of a fibrous pseudocapsule in most areas, in contrast to nephroblastoma, and the infiltrating strands of tumor peripherally.

Fig. 1.53

Fig. 1.54

Fig. 1.55

Fig. 1.56

Fig. 1.57

Figs 1.53–1.58 Photomicrographs of nephrectomy specimens of clear cell sarcoma of kidney showing the range of morphological appearances, including sheets of bland, monomorphic cells, markedly nested architecture and mucoid/myxoid variants.

Immunohistochemical staining

• Importantly, in the differential diagnosis with other pediatric renal malignancies

cytokeratin, WT1, CD99 staining is negative

vimentin staining does not reveal the dot-like pattern of renal rhabdoid tumor

Epidemiology

• Predominantly a tumor of young children

average age at diagnosis 1 year, 80% aged < 2 years, 60% < 1 year

Genetics

• Gene important for chromatin remodeling

inactivation is tumorigenic

• Wide range of mutations, deletions or chromosome losses

therefore no readily available RT-PCR based assay yet

• Some patients may be germline mutation carriers of gene defects

increased risk of malignant embryonal tumors of the posterior fossa

may be a family history of other malignancies

Clinical features

Macroscopic features (Fig 1.59)

Fig 1.59 Macroscopic photograph of a nephrectomy specimen containing a malignant renal rhabdoid tumor, demonstrating a partially necrotic tumor with viable areas composed of solid cream areas with focal hemorrhage.

Histopathological features (Figs 1.60–1.64)

• Characteristic morphological features of tumor cells

open vesicular nuclei

prominent nucleoli

scattered hyaline eosinophilic cytoplasmic inclusions

• Proportion of cells demonstrating morphological rhabdoid features of eosinophilic inclusions, may be highly variable

some demonstrate large number of such inclusion-bearing cells

others (particularly extrarenal rather than renal RTs), may be composed of predominant undifferentiated small round cells in a myxoid background

– only focal ‘classical’ rhabdoid phenotype

Fig. 1.60

Fig. 1.61

Fig. 1.62

Fig. 1.63

Figs 1.60–1.64 Photomicrographs of nephrectomy specimens of malignant renal rhabdoid tumor demonstrating the sheet-like and infiltrative pattern of growth, composed of uniform, large, ovoid tumor cells with vesicular nuclei prominent nucleoli. Characteristic ‘rhabdoid’ inclusions are variably frequent.

Immunohistochemical staining (Figs 1.65, 1.66)

• INI1 immunostaining characteristically absent in the nucleus of RT cells

INI1 staining positive in the nucleus of almost all other pediatric tumors (Hoot et al 2004)

INI1 immunostaining now provides a definitive marker for this tumor in the appropriate context

– note that medullary renal carcinoma and some cells of synovial sarcoma may also be INI1 negative

Fig. 1.65

Figs 1.65–1.66 Photomicrographs of nephrectomy specimens of malignant renal rhabdoid tumor demonstrating characteristic ‘dot-like’ cytoplasmic expression of vimentin (Fig 1.65) and essentially diagnostic lack of nuclear expression of INI1 in the presence of appropriate positive normal control tissue (Fig 1.66).

Epidemiology

• Caution in diagnosis in older patients

may represent other spindle cell mesenchymal tumors

Genetics

• Cellular, but not classical, congenital mesoblastic nephroma demonstrates a t(12;15)(p13;q25) ETV6-NTRK3 translocation

identical to that associated with

– congenital/infantile fibrosarcoma

– secretory carcinoma of the breast

Clinical features

Macroscopic features (Figs 1.67–1.70)

Fig. 1.67

Fig. 1.68

Figs 1.67–1.69 Macroscopic photographs of nephrectomy specimen containing mesoblastic nephroma, demonstrating predominantly solid, form, pale-cream tumors which diffusely infiltrate the junction with normal kidney.

Fig 1.70 Macroscopic photograph of a slide from a nephrectomy specimen containing a mesoblastic nephroma, in this case demonstrating marked areas of hemorrhage and cystic change, which may occasionally be present.

Histopathological features (Figs 1.71–1.82)

• Classical subtype (25–50% of cases)

appearance similar to that of other infantile fibromatoses

composed of bland spindle cells in a variably collagenous stroma

focally marked interlacing fascicular pattern

infiltration of native renal elements at the edge of the tumor

• Cellular subtype (40–60% of cases)

morphologically indistinguishable from an infantile fibrosarcoma

solid sheets of ovoid tumor cells with relative reduction in cytoplasm, increased cellularity, mitoses and even focal necrosis

• Mixed subtype (<10% of cases)

clearly demonstrate some areas showing a classical pattern and others showing a cellular pattern

• Tumor subtype of importance

majority of cases with recurrence have been cellular, associated with the presence of the abnormal gene fusion product

Fig 1.71 Photomicrograph of a needle core biopsy of a mesoblastic nephroma showing tumor composed of interlacing fascicles of bland spindle cells with entrapped tubular elements.

Fig 1.72 Photomicrograph of nephrectomy specimens of a mesoblastic nephroma showing the previous biopsy site, with ‘gelfoam’ injected.

Fig. 1.73

Fig. 1.74

Fig. 1.75

Fig. 1.76

Fig. 1.77

Fig. 1.78

Fig. 1.79

Figs 1.73–1.80 Photomicrographs of nephrectomy specimens of classical mesoblastic nephromas, demonstrating tumor composed of interlacing fascicles of bland spindle cells. Note the presence of cartilage focally and the infiltrating margin with normal kidney and the surrounding fat.

Fig. 1.81

Figs 1.81–1.82 Photomicrographs of nephrectomy specimens of cellular (Fig 1.81) and mixed type (Fig 1.82) mesoblastic nephromas. The cellular subtype is composed of closely-packed plump ovoid cells, superficially resembling other blastematous tumors. In mixed variants, both morphological subtypes are present.

Immunohistochemical staining

Clinical features

Histopathological features (Figs 1.83–1.87)

Fig 1.83 Macroscopic photograph of a pediatric renal cell carcinoma showing a well-circumscribed, solid intra-renal tumor.

Fig. 1.84

Fig. 1.85

Fig. 1.86

Figs 1.84–1.87 Photomicrographs of nephrectomy specimens of cases of pediatric renal cell carcinoma, showing solid, papillary, clear cell and chromophobe phenotypes.

Immunohistochemical staining

• May also express EMA, vimentin and CEA

extent of expression varying with tumor subtype

Epidemiology

Genetics

• Entity, although having highly suggestive histopathological features, is defined by the presence of a somatic chromosomal abnormality

region Xp11.2 and the TFE3 gene (Argani et al 2001)

• MITF-TFE3 translocations result in marked nuclear overexpression of the TFE3 protein

detectable as strong diffuse nuclear immunostaining which is essentially diagnostic in this setting

Clinical features

Macroscopic features

Histopathological features (Figs 1.88–1.90)

• Fairly characteristic histopathological appearance

florid papillary architecture with numerous clear cells, or cells with markedly granular eosinophilic cytoplasm

• Some correlation between histopathological features and the exact gene fusion involved

ASPL-TFE3 associated carcinomas mainly clear cells with open vesicular nuclei and prominent nucleoli, often with psammoma body formation

PRCC-TFE3 associated carcinomas more nested and compact architecture

Fig. 1.88

Fig. 1.89

Figs 1.88–1.90 Photomicrographs of nephrectomy specimens of cases of molecular proven Xp1-associated pediatric renal cell carcinoma, showing marked papillary architecture with numerous clear cells.

Immunohistochemical staining

Genetics

• TFEB and TFE3 members of the same transcription-factor family

t(6;11) tumors may be closely related to Xp1.1 translocation RCCs

Histopathology (Figs 1.91–1.93)

Fig. 1.91

Fig. 1.92

Figs 1.91–1.93 Photomicrographs of a nephrectomy specimen of a case of molecular proven t(6;11)-associated pediatric renal cell carcinoma, showing predominant clear cells.

Immunohistochemical staining

Epidemiology

Genetics

Clinical features

Macroscopic features

Histopathological features

• May be similar to other renal cell carcinomas but often unusual features

solid and papillary architecture

prominent cells having eosinophilic cytoplasm, oncocytoid

Immunohistochemical staining

Clinical features

Macroscopic features

Histopathological features

• Collecting duct carcinoma demonstrates high-grade nuclear features

atypia

prominent nucleoli

Immunohistochemical staining

Epidemiology

Genetics

• Expression profiling studies indicate a distinct molecular signature of renal medullary carcinoma

clusters more closely with transitional cell carcinoma of the renal pelvis rather than renal cell carcinoma (Yang et al 2004)

Clinical features

• Survival poor (mean <20 weeks from diagnosis)

some survivors in the minority (<5%) with localized disease at presentation (Simpson et al 2005)

Macroscopic features

Histopathological features (Figs 1.94–1.98)

• Sheets and nests of cells with prominent nucleoli and central clearing within a variably collagenous stroma

cellular morphology resembles malignant RRT

• In areas, the tumor may appear poorly differentiated

sheets of cells showing marked nuclear polymorphism

Fig. 1.94

Fig. 1.95

Fig. 1.96

Fig. 1.97

Figs 1.94–1.98 Photomicrographs of a nephrectomy specimen of a case of renal medullary carcinoma in a teenage girl with sickle cell trait showing a diffusely infiltrative tumor composed of sheets, nests and tubular structures of large ovoid cells with prominent nucleoli. Focally, there may be a marked inflammatory infiltrate and myxoid stromal change.

Immunohistochemical staining (Fig 1.99)

• VEGF and HIF expression

possible link to hypoxia related to pathogenesis (Swartz et al 2002)

Fig 1.99 Photomicrograph of a nephrectomy specimen of a case of renal medullary carcinoma showing lack of nuclear expression of INI1, reminiscent of malignant rhabdoid tumor.

Genetics

• No specific genetic diagnostic changes

some show loss of the Y chromosome and gain of chromosome 7 and 17, similar to papillary renal cell carcinomas

Clinical features

Macroscopic features

Histopathological features

• Characteristic histopathological appearance

complex tubulopapillary areas of stromal cores covered by a single layer of bland epithelial cells

Epidemiology

Genetics

Clinical features

Macroscopic features

Histopathological features

• Characteristic histopathological appearance

sheets, nests or tubules of polygonal cells with granular eosinophilic cytoplasm

round nuclei with no nuclear atypia

Immunohistochemical staining

Electron microscopy

Epidemiology

Genetics

Clinical features

Macroscopic features

Histopathological features (Figs 1.100–1.103)

• Metanephric adenoma shows regular, closely packed tubular structures composed of small uniform ovoid cells with no nuclear atypia

branching or angulated tubular structures may also be seen

variable adenomatous to collagenous background may be present

psammoma bodies may be seen

• Metanephric adenofibroma has areas histologically indistinguishable from a metanephric adenoma

in addition, has a spindle cell component

– fibroblast-like cells set within a variably collagenous stroma

focal hyaline and myxoid change may also be seen

areas of specialized stromal differentiation are uncommon but have been reported (see metanephric stromal tumor section)

variable histological appearance with either predominance of epithelial areas or spindle cell areas (Arroyo et al 2001)

Fig. 1.100

Figs 1.100–1.101 Photomicrographs of metanephric adenofibroma showing presence of both well-differentiated epithelial and stromal areas.

Fig 1.102 Photomicrograph of metanephric adenofibroma highlighting the epithelial element (metanephric adenoma-like) with regular, closely packed tubular structures composed of small uniform ovoid cells with no nuclear atypia.

Fig 1.103 Photomicrograph of metanephric adenofibroma highlighting the stromal element (metanephric stromal tumor-like) with fibroblast-like cells in a variably collagenous stroma. There is condensation around an entrapped tubule and this appearance somewhat resembles mesoblastic nephroma.

Immunohistochemical staining

• Note: there may be nuclear expression of WT1 in the epithelial areas of metanephric adenomas and adenofibromas

not to be confused with Wilms’ tumor (Muir et al 2001)

Epidemiology

Genetics

Clinical features

Macroscopic features

Histopathological features

• Other histopathological findings related to tumor cell interaction with entrapped non-neoplastic renal elements

spindle cell surrounding of tubules and blood vessels

– forming characteristic onion-skin type appearance

marked nodular variations in tumor cellularity

striking angiodysplasia-type changes may be seen

– affecting intratumoral vessels

juxtaglomerular cell hyperplasia

• 20% demonstrate marked heterologous differentiation

in particular glial or cartilaginous nodules (Argani & Beckwith 2000)

Immunohistochemical staining

Epidemiology

Genetics

Clinical features

Macroscopic features

Histopathological features

• Morphological findings characteristic

network of eosinophilic, hyaline stromal osteoid-type material with intermixed osteoblast-like cells and spindle cell stroma

Immunohistochemical staining

Epidemiology

• Association with tuberose sclerosis, particularly when presenting in childhood

however, in children with tuberose sclerosis other renal manifestations are far more common, including:

– glomerular cystic disease

– tuberose sclerosis associated renal cystic disease

– renal hamartomas

Genetics

• Genetic basis of tuberose sclerosis is well described

loss of heterozygosity of part of the TSC2 gene may be seen in both sporadic and tuberose sclerosis associated tumors

Clinical features

Macroscopic features

Histopathological features

• Characteristic mixture of:

mature adipose tissue

thick walled abnormal blood vessels

smooth muscle

• Subtypes may occur

epithelioid angiomyolipoma

– more infiltrative and hemorrhagic, with marked proliferation of highly pleomorphic epithelioid cells

Immunohistochemical staining

• As part of the characteristic PEComa group of lesions

angiomyolipomas characteristically express HMB45 and smooth muscle markers such as smooth muscle actin

Epidemiology

Genetics

Clinical features

Macroscopic features (Figs 1.104, 1.105)

Fig 1.104 Macroscopic photograph of a primary renal PNET, demonstrating a hemorrhagic and necrotic tumor mass.

Fig 1.105 Macroscopic photograph of an excised intracardiac extension of primary renal PNET; such lesions are well reported to extend into the renal vein and vena cava.

Histopathological features (Fig 1.106)

• Histopathological features of renal PNET same as PNETs at any other site

sheets, nests and rosette type structures of small ovoid cells with finely dispersed chromatin and a high nuclear to cytoplasmic ratio

Fig 1.106 Photomicrograph of a primary renal PNET demonstrating tumor composed of sheets of monomorphic ‘small ovoid cells’ with little cytoplasm, morphologically non-diagnostic.

Immunohistochemical staining (Fig 1.107)

Fig 1.107 Photomicrograph of a primary renal PNET demonstrating strong uniform membranous CD99 expression.

Electron microscopy

Epidemiology

Genetics

• t(X;18) SYT fusion transcript product

may be detected using FISH or RT-PCR

– useful in making a definitive diagnosis on a limited specimen

Clinical features

Macroscopic features

Histopathological features

Immunohistochemical staining

Additional investigations

• Majority of renal synovial sarcomas have a monophasic, spindle cell appearance

corresponds to the presence of the SYT-SSX2 fusion transcript product

Epidemiology

Genetics

• As with other neuroblastic tumors, a range of molecular biological markers are related to prognosis

including MYCN status, chromosome 1p loss and chromosome 17q gains (see tumor chapter)

Clinical features

• Presentation similar to other primary renal tumors, although elevated levels of catecholamine may be reported

should be noted that normal catecholamine levels does not exclude the diagnosis

– a minority of neuroblastic tumors may be associated with normal urinary VMA concentrations

Macroscopic features

• No distinctive macroscopic features of primary intrarenal neuroblastoma

in many cases the tumor appears markedly necrotic and hemorrhagic

Histopathological features

• Diagnostic histopathological features similar to those of neuroblastomas at other sites

most cases reported to arise within the kidney have been of undifferentiated subtype

– rarely show significant ganglion cell differentiation, neuropil or Schwannian stroma

Immunohistochemical staining

• Immunohistochemical staining is very useful in the diagnosis of intrarenal neuroblastoma

CD56 positive, NB84 positive and WT1 negative

Additional investigations

Epidemiology

Genetics

Clinical features

Macroscopic features

Histopathological features (Figs 1.108, 1.109)

• Chondroid differentiation in three-quarters

islands of hyaline cartilage

focal chondroid matrix

Fig. 1.108

Figs 1.108–1.109 Photomicrographs of an anaplastic sarcoma of kidney demonstrating spindle cell areas with marked pleomorphism and focal chondroid differentiation.

Immunohistochemical staining

Additional investigations

Overview

• Main difference in the pediatric setting being the relative frequencies of the conditions being considered within the differential diagnosis

many entities common in adulthood, such as diabetic nephropathy and hypertension-related changes, are extremely uncommon in childhood

range of conditions which may be encountered in pediatric biopsy practice which are rarely, if ever, seen in adulthood, for example congenital nephrotic syndrome

• Within a given clinicopathological category, such as patients presenting with nephrotic syndrome, the relative frequency of underlying diagnoses may be quite different in pediatric compared to adult practice

membranous nephropathy, for example, is a common cause of nephrotic syndrome in adulthood but primary membranous nephropathy represents only a tiny proportion of children presenting with nephrotic syndrome

General approach

• Various suggested approaches to interpretation of a renal biopsy specimen, all of which are essentially based around a systematic approach

examine the various renal components in turn

collate the findings in conjunction with the clinical history and results of additional investigations

• Aims of examination of the renal biopsy are to provide two main pieces of information for the clinician

underlying diagnosis

amount of chronic damage present

– single most important factor regarding long-term renal prognosis

• Note, many conditions which may be biopsied in childhood require electron microscopy for the definitive diagnosis

recommended that material will be routinely made available and processed for electron microscopic examination in all cases of pediatric renal biopsies obtained for primary diagnosis of renal disease

An approach to the biopsy

• Initial review to determine whether kidney is present

if so whether it is cortex and medulla

• Estimation of the degree of chronic change

interstitial fibrosis

tubular atrophy

• Total number of glomeruli present

number which are globally or segmentally sclerosed

• Glomeruli systematically examined:

focal or diffuse changes

– which affect only some or the majority of glomeruli respectively

global or segmental changes

– affecting the whole glomerulus or only part of it, respectively

Specific entities

• Nephrotic syndrome

Minimal change nephropathy

Focal segmental glomerular sclerosis (FSGS)

Membranous nephropathy

Congenital and infantile nephrotic syndrome

Lupus nephritis

Post infectious glomerulonephritis

Membranoproliferative glomerulonephritis (MPGN)

Other rare

• Nephritic syndrome/acute renal failure

Acute tubular necrosis/damage

Hemolytic uremic syndrome

Henoch–Schonlein nephritis

Vasculitic glomerulonephritis

Lupus nephritis

Goodpasture’s syndrome

Cryoglobulinemic glomerulonephritis

Post infectious glomerulonephritis

Membranoproliferative glomerulonephritis

Acute interstitial nephritis

• Chronic renal failure

Developmental abnormalities/dysplasia

Metabolic disease

Juvenile nephronophthisis

Glomerulonephritis

Diabetes mellitus (rare in childhood)

• Isolated hematuria

Thin glomerular basement membrane disease

Alport nephropathy

IgA nephropathy

• Transplant pathology

Acute rejection

Chronic rejection

Drug related changes

Infection

Lymphoproliferative disorder

Clinical features

• More common in boys

2 : 1 M : F

• Nephrotic syndrome is main feature

microscopic hematuria in 10–30%

hypertension in 20%

rarely associated with reduced renal function at presentation

• Acute renal failure rare complication

usually due to acute tubular necrosis presumed due to altered hemodynamics and hypovolemia

Histopathological features (Figs 1.110, 1.111)

• Glomeruli show no morphological abnormalities on routine light microscopy

very mild mesangial hypercellularity described

– more common in those with hematuria

– may be associated with poorer initial response to therapy and more frequent relapses

Fig. 1.110

Figs 1.110–1.111 Photomicrographs of a renal biopsy with minimal change nephropathy with no significant abnormalities on light microscopy and normal glomerular capillary walls.

Immunohistochemical staining

Electron microscopy

Differential diagnoses and pitfalls

• Main differential diagnoses are:

IgM nephropathy/C1q nephropathy

– uncertain whether variant MCN or FSGS; see below (Fukuma et al 2006)

FSGS

– ensure that deep cortical glomeruli are present

– issues of sampling

C1q nephropathy

• Idiopathic glomerulonephritis characterized by:

mild mesangial expansion

mesangial deposition of C1q

– in the absence of other diagnoses such as lupus nephritis

• May morphologically mimic lupus nephritis (Sharman et al 2004)

• Possible variant of MCN or FSGS (Kersnik Levart et al 2005, Lau et al 2005, Markowitz et al 2003)

• Presents with steroid resistant/dependent nephrotic syndrome or severe proteinuria

• Outcome dependent on morphological features of either MCN or FSGS

IgM nephropathy

• Idiopathic glomerulonephritis characterized by:

mesangial expansion and hypercellularity

isolated diffuse mesangial IgM deposits

• Possible variant of MCN or FSGS (Myllymauki et al 2003)

• Behavior appears to be MCN-like in the absence of morphological features of FSGS (Al-Eisa et al 1996)

Clinical features

• Nephrotic syndrome

generally older presentation than those with minimal change disease

microscopic hematuria in up to 50%

hypertension and renal insufficiency more common than minimal change disease

• A subgroup may be familial due to autosomal recessive and dominant conditions

especially early onset cases

usually related to podocyte-related proteins (podocytopathies) such as nephrin, podocin and alpha-actinin (see later sections)

• Other syndromic associations include:

WT1 mutations

– affect podocyte structure

· diffuse mesangial sclerosis

· Denys–Drash syndrome

· Frasier syndrome

Nail patella syndrome

Galloway–Mowat syndrome and others

Histopathological features (Figs 1.112–1.116)

• Glomerular lesions are characteristically

focal

– affecting only some glomeruli

segmental

– affecting only part of the glomerulus

• Sclerotic lesions more common at the periphery of the glomerulus

with or without capsular adhesions

• Sclerotic lesion obliterates glomerular capillary lumens and distorts the architecture

with or without hyaline deposits

• Uninvolved glomeruli characteristically:

morphologically normal

morphometrically enlarged

• At the time of initial biopsy usually only a minority of glomeruli apparently involved

increases if glomeruli are serially sectioned

• Sclerotic lesion may affect

glomerular hilum

glomerular tuft at the origin of the proximal tubules

most cases, lesions appear to be admixture of locations

• Diffuse mesangial hypercellularity and expansion present in around a third of cases

clinical significance remains unclear

• Sclerotic lesions may be associated with focal tubular atrophy and interstitial fibrosis

any tubular atrophy is abnormal in childhood and in the context of a patient with nephrotic syndrome should stimulate a thorough search for associated glomerulosclerosis

Fig 1.112 Photomicrograph of a renal biopsy with primary idiopathic FSGS, demonstrating a patchy area of tubular atrophy and interstitial fibrosis. In this clinical setting in a pediatric renal biopsy, such changes should prompt a thorough search for sclerotic glomerular lesions.

Fig 1.113 Photomicrograph of a renal biopsy with primary idiopathic FSGS, demonstrating a ‘foam-cell’ accumulation, a feature associated with heavy proteinuria of many causes.

Fig. 1.114

Figs 1.114–1.115 Photomicrographs of renal biopsies with primary idiopathic FSGS, demonstrating segmental glomerular sclerosing lesions with other parts of the glomeruli appearing morphologically unremarkable.

Fig 1.116 Photomicrograph of renal biopsies staining with silver highlighting the segmental sclerotic lesion. Note also the prominent epithelial cells around the sclerotic area.

Morphological variant types

Mesangial hypercellularity

• Clinical significance unknown, inconsistent results from published studies

Tip lesion

• Lesion adjacent to the proximal tubular opening / prolapsing into tubule

glomerular foam cells or hyalinization

proximal epithelial changes

• Possible early lesion of classical FSGS with subsequent progression

• Coexistence of classical FSGS lesions with tip lesions in some cases

• When isolated may represent a variant of MCN or FSGS

appears to respond better to therapy than classical FSGS (Stokes et al 2004)

Collapsing glomerulopathy

• See section below

Immunohistochemical staining

Electron microscopy

Differential diagnoses and pitfalls

• Patients with long standing steroid resistant nephrotic syndrome treated with immunosuppressive agents such as ciclosporin, may show sclerotic glomerular lesions

either represent the primary underlying diagnosis of FSGS or secondary to therapy

in this context, other features of calcineurin-inhibitor associated changes should be specifically searched for and commented on (see transplant rejection section)

• Secondary FSGS

morphological examination alone cannot distinguish between primary and secondary FSGS

Histological prognostic features in FSGS

• Many morphological features have been suggested to be associated with better or worse outcome

only finding consistently associated with outcome in terms of progression to end stage renal disease, is the extent of chronic tubulointerstitial change

most important glomerular finding to identify is presence of cellular lesion / collapsing glomerulopathy

Epidemiology

• Primary collapsing glomerulopathy

increased in Afro-Caribbeans

usually in adults but reported in children

• Secondary collapsing glomerulopathy

HIVAN

autoimmune disease / lupus

hematological malignancy

drug-related

parvovirus related (Moudgil et al 2001)

familial variant now reported (Avila-Casado et al 2003)

Clinical features

• Nephrotic syndrome

rapidly progressive

– 70% progress to end stage renal disease by average 20 months

Histopathological features (Figs 1.117–1.120)

• Tubulointerstitial damage

interstitial fibrosis

tubular atrophy

patchy tubular dilation

Fig. 1.117

Fig. 1.118

Fig. 1.119

Figs 1.117–1.120 Photomicrographs of renal biopsies from a child with probable familial ‘collapsing’-type FSGS, demonstrating marked and widespread irreversible chronic changes, patchy tubular dilation and widespread glomerular sclerosis with shrinkage of the tufts and striking glomerular epithelial cell prominence.

Immunohistochemical staining

Differential diagnoses and pitfalls

Genetics

• NPHS2 podocin mutations

numerous different mutations reported

Clinical features

• Early onset or infantile, steroid resistant nephrotic syndrome

not usually present at birth

rapid progression to end stage renal disease

Histopathological features

Differential diagnoses and pitfalls

• Recent cases of possible AR FSGS also identified in mice and case reports in humans associated with CD2AP mutations

relevance to human disease not yet established

Epidemiology

Genetics

Clinical features

• Heterogeneity both within and between families

some with early presentation and rapid progression to end stage renal disease

Histopathological features