Nephroblastoma

• Malignant embryonal renal neoplasm recapitulating nephrogenesis; the most common malignant renal tumour of childhood.
• Mostly under 5 years; congenital, adolescent and rare adult cases occur.
• Classic triphasic: blastema, epithelium and stroma in very different proportions; some tumours are monophasic.
• Blastema: densely packed small round blue cells, nuclear overlapping, high N:C ratio.
• Epithelium: primitive tubules, rosettes, glomeruloid structures, papillae, mature tubules. Stroma: fibroblastic, myxoid, smooth or skeletal muscle, cartilage, bone, fat.
• Anaplasia, especially diffuse, is the most important adverse histological feature.
• Nephrogenic rests often coexist and indicate developmental and hereditary predisposition.
• Heterogeneous molecular pathogenesis: renal development, WNT, 11p15 imprinting, microRNA processing, chromatin regulators.
• Risk classification depends on whether the tumour was treated before surgery; COG and SIOP are not interchangeable.

Diagnostic pearl: Wilms tumour is defined by embryonal renal differentiation, not by finding all three components; a monophasic tumour needs a more demanding differential.

Clinical

• Painless abdominal or flank mass; pain, haematuria, hypertension or constitutional symptoms; a minority bilateral; genitourinary anomalies or predisposition syndromes.

Gross

• Well-demarcated, pushing, lobulated, tan-grey or tan-pink fleshy mass; haemorrhage, cysts, necrosis; pseudocapsule of compressed kidney and fibrous tissue.

Extension

• Renal sinus soft tissue, renal vein, perinephric fat and capsular penetration are staging findings; rupture and spill matter; examine the background kidney for multifocality and rests.

Diagnostic pearl: in Wilms tumour the gross examination is staging: capsule, sinus, vessels, margins and background kidney all count.

• Blastema: small round blue cells in sheets, nests, cords or nodules, sometimes with rosettes.
• Epithelium: primitive tubules, acini, glomeruloid structures, rosettes, more differentiated tubules.
• Stroma: spindle or stellate cells in fibrous or myxoid matrix, possibly heterologous.

Low power

• Blastemal nodules alternating with epithelial or stromal areas; lobulation; abrupt or gradual transitions; tubules within blastema; stroma at the periphery.

Limits

• One component may dominate; triphasic areas may be few; biopsies miss components; chemotherapy changes proportions.

Diagnostic pearl: look for a coherent spectrum of embryonal nephrogenic differentiation, not just three cell types.

• Small to intermediate cells, scant basophilic cytoplasm, high N:C ratio, round to oval hyperchromatic nuclei, fine chromatin, small nucleoli, frequent mitoses.
• Diffuse: featureless sheets mimicking other small round cell tumours.
• Nested: aggregates separated by thin septa or vessels, vaguely organoid.
• Serpentine / cord-like: elongated cords merging into tubules or rosettes.
• Basaloid: peripheral palisading, mimicking basaloid carcinoma.
• Rosette-like: early epithelial differentiation, not necessarily neuroendocrine.
• Nuclear overlapping, apoptotic bodies and mitoses; primitive tubules may need extensive search.

Diagnostic pearl: pure blastemal Wilms tumour mimics neuroblastoma, Ewing sarcoma and other round cell tumours; a directed IHC and molecular work-up is essential.

• Primitive tubules: small round or angulated, cuboidal cells, tiny lumina, branching; within blastema or myxoid stroma.
• Glomeruloid structures: tufts resembling developing glomeruli, some quite mature.
• Rosette-like structures: mimic neuroepithelial rosettes in blastemal tumours.
• Mature epithelium: cuboidal or columnar tubules, collecting duct-like.
• Cytology may be bland and uniform; mature areas resemble metanephric adenoma or papillary neoplasms.

Diagnostic pearl: epithelial-predominant Wilms tumour can be deceptively bland; primitive nephroblastic differentiation and its relation to other components matter more than atypia.

• Fibroblastic: bland spindle cells in short fascicles, collagen; fibroma-like.
• Myxoid: stellate cells in pale basophilic matrix with dispersed tubules.
• Cellular: compact spindle cells, mitoses; resembles cellular CMN.
• Smooth muscle: eosinophilic fascicles, SMA/desmin.
• Stromal-predominant: little blastema, sparse epithelium; common after preoperative chemotherapy, which removes blastema.

Diagnostic pearl: a childhood renal spindle-cell tumour with occasional tubules is not automatically Wilms tumour; consider CMN and metanephric stromal tumour.

• Rhabdomyomatous differentiation can be very prominent (fetal rhabdomyomatous phenotype).
• Cartilage and bone are compatible with Wilms tumour and are not sarcoma; heterologous tissue can obscure the nephroblastoma, so sample for blastema or primitive epithelium.

Diagnostic pearl: skeletal muscle, cartilage or bone can be part of Wilms tumour; heterologous differentiation is not sarcoma.

• Blastemal: confluent small blue cells with little or no epithelium; mimics Ewing sarcoma, neuroblastoma, lymphoma; WT1 and renal developmental markers support; molecular testing may be needed to exclude fusion-defined round cell tumours.
• Epithelial: primitive or mature tubules, glomeruloid structures, minimal atypia; mimics metanephric adenoma or PRCC, especially on biopsy.
• Stromal: spindle or heterologous tissue with sparse blastema and epithelium; mimics CMN, CCSK or other spindle tumours; common after treatment.

Diagnostic pearl: no visible triphasic pattern does not exclude Wilms tumour, but a monophasic diagnosis requires excluding molecularly distinct paediatric renal tumours.

• Abundant fetal-type skeletal muscle: spindle to elongated rhabdomyoblasts, eosinophilic cytoplasm, some cross-striations; limited primitive epithelium and inconspicuous blastema.
• Often young children; bilateral cases; developmental or predisposition settings.
• Differential: embryonal rhabdomyosarcoma, CMN with unusual differentiation, other mesenchymal tumours.
• A descriptive pattern, not a WHO risk category; does not imply anaplasia or high risk.

Diagnostic pearl: extensive muscle can make the tumour look purely mesenchymal; finding the nephroblastic epithelium is essential.

• Teratoid Wilms tumour: extensive heterologous tissue (squamous, intestinal glands, muscle, cartilage, bone, fat, neural); can resemble immature teratoma; sampling usually shows classic nephroblastoma; exclude rare intrarenal teratoma or germ cell tumour.
• Teratoid and fetal rhabdomyomatous patterns are descriptive, not COG or SIOP risk groups.

Diagnostic pearl: an unusual tissue is not a separate entity; the question is whether it is nephroblastoma with heterologous differentiation.

• Cystic Wilms tumour: dilated epithelial spaces with blastema in septa and solid areas; separate from paediatric cystic nephroma and CPDN.
• Botryoid growth: grape-like polypoid masses into the pelvis; still nephroblastic; mimics a pelvic soft tissue malignancy.
• Pseudopapillary change: discohesion around vessels; not papillary RCC.

Diagnostic pearl: a cystic renal mass with primitive septal elements needs extensive sampling to separate Wilms tumour from CPDN.

• All three: nuclei at least 3× the diameter of adjacent non-anaplastic nuclei of the same type; marked hyperchromasia; multipolar or tripolar mitoses.
• Can occur in blastema, epithelium or stroma.

Pitfalls

• Large nuclei or prominent nucleoli alone are not anaplasia; post-chemotherapy degenerative atypia differs from viable anaplasia; pleomorphism without multipolar mitoses is not anaplasia.

Diagnostic pearl: anaplasia is a specific triad, not just high nuclear grade.

• Focal: one or a few sharply demarcated intrarenal foci, none extrarenal, no significant nuclear unrest elsewhere; needs extensive sampling.
• Diffuse: anything failing focal criteria, including multiple ill-defined areas, extrarenal or metastatic anaplasia, or anaplasia on a random biopsy.
• Nuclear unrest: atypia short of anaplasia; not anaplasia, but widespread unrest can prevent a focal classification.

Diagnostic pearl: focal anaplasia is a distributional diagnosis that needs adequate sampling.

• TP53 alteration (mutation, 17p loss, other mechanisms) is particularly associated with diffuse anaplasia, but not present in every anaplastic tumour.
• p53 IHC: strong diffuse (missense-type) or complete loss with internal controls (null-type) suggests alteration; wild-type staining does not exclude it; aberrant p53 does not diagnose anaplasia.
• TP53 changes can emerge late; anaplastic and non-anaplastic areas can differ molecularly.
• Diffuse anaplasia predicts treatment resistance; histological criteria remain fundamental.

Diagnostic pearl: TP53 mutation and anaplasia are associated, not synonyms; morphology establishes anaplasia.

• Untreated blastemal-predominant tumour is not equivalent to high-risk post-chemotherapy blastemal type.
• Treated tumours can be necrotic with preserved stroma or epithelium; residual viable blastema matters most after SIOP chemotherapy.
• Always document whether preoperative therapy was given.

Diagnostic pearl: applying SIOP residual-blastema thresholds to an untreated nephrectomy gives the wrong risk.

• With less than about two-thirds regression: blastemal = more than two-thirds of viable tumour is blastema; epithelial or stromal = more than two-thirds of that component with no more than 10% blastema; otherwise mixed.
• Percentages refer to viable tumour, after first deciding the degree of regression.

Diagnostic pearl: ask how much regressed, then what proportion of what remains is blastema.

• Necrosis: acellular areas, ghost outlines, karyorrhexis, calcification, inflammation.
• Fibrosis: broad hypocellular scars with scattered residual tumour.
• Foamy macrophages: sheets that can hide small residual nests.
• Haemorrhage and haemosiderin: heterogeneous cut surface.
• Maturation: blastema matures into epithelium or stroma; more skeletal muscle.
• Residual blastema: small blue nests in regressed tumour; identify and quantify.

Diagnostic pearl: treatment-induced change is not spontaneous necrosis; apply the right treatment-specific framework.

• SIOP WT 2001 analysis (2026): 3,459 unilateral tumours, absolute blastemal volume available for 1,802.
• Residual blastemal volume was independently associated with event-free and overall survival.

Thresholds come from this dataset; they may refine future risk stratification but are not WHO diagnostic criteria.

Diagnostic pearl: two tumours with the same blastemal percentage can carry very different absolute blastemal burdens.

• WT1 is most useful in blastema and primitive epithelium; negative WT1 does not exclude Wilms tumour, and other renal tumours express it.
• PAX8 supports renal developmental differentiation and can label blastema; not specific.
• Keratins mark epithelium and may be weak in blastema; keratin negativity does not exclude blastemal Wilms tumour.
• Myogenic markers in compatible nephroblastoma do not mean rhabdomyosarcoma.

Diagnostic pearl: no single marker proves or excludes Wilms tumour; interpret by compartment.

• Not universal: a minority are WT1-negative, depending on molecular subtype and differentiation.
• Metanephric adenoma is also strongly WT1+, with tubules and glomeruloid structures.
• Compartment-dependent: blastema and epithelium differ; heterologous stroma may be negative.
• Other WT1+ tumours: DSRCT (antibody epitope matters), mesothelial and serosal tumours, some ovarian and renal tumours.
• Molecular: WT1 alterations occur in a subset only; wild-type WT1 does not exclude Wilms tumour.

Diagnostic pearl: WT1 marks a differentiation programme, not Wilms tumour specifically.

• WT1 (11p13): altered in about 10–20% of sporadic tumours, often with CTNNB1; germline variants cause syndromes.
• 11p15: loss of imprinting or UPD increases IGF2; Beckwith-Wiedemann spectrum.
• MicroRNA genes: a route independent of WT1/WNT. SIX1/SIX2: activating changes sustain blastema.

Diagnostic pearl: Wilms tumour is not synonymous with WT1 mutation; several pathways converge on the same phenotype.

• 1q gain: consistent adverse marker, strongest in upfront-nephrectomy cohorts; protocol-dependent use.
• Combined 1p/16q LOH: used in COG risk-adapted therapy; uncommon.
• 11p15: initiation and predisposition; possibly prognostic in very-low-risk surgery-only cohorts.
• TP53, MYCN: adverse associations; weigh against histology, stage and treatment.

A 2026 systematic review (JCO Precision Oncology) found the strongest adjusted evidence for 1q gain and 1p/16q loss in upfront-nephrectomy settings, less in preoperatively treated populations.

Diagnostic pearl: a marker's prognostic value depends on the COG-like or SIOP-like treatment pathway.

• Clues: bilateral or multifocal disease, multiple rests, very young age, anomalies, overgrowth, family history.

Diagnostic pearl: unilateral disease does not exclude predisposition; bilateral disease strongly prompts genetic evaluation.

• Persistent foci of embryonal nephrogenic tissue beyond normal nephrogenesis; precursor lesions, not invasive tumour.
• Blastemal, epithelial and stromal elements; less expansile; can be dormant, hyperplastic or regressing.
• Single or multiple, possibly bilateral; diffuse multifocal rests = nephroblastomatosis.
• Markers of susceptibility with different syndromic correlations by type.

Diagnostic pearl: rests and Wilms tumour can look cytologically identical; architecture, relation to the kidney and expansile growth separate them.

Diagnostic pearl: rest distribution gives molecular and hereditary clues, but does not establish a syndrome on its own.

Hyperplastic rest

• Increased cellularity, enlarged nodule, keeps a relationship with native structures, usually no expansile encapsulated mass.

Wilms tumour

• Expansile mass, pseudocapsule or compressed interface, displaces or destroys kidney, mixed compartments, necrosis, anaplasia or infiltration.

• Rests can grow large; small Wilms tumours may lack a pseudocapsule; treatment alters morphology; no IHC separates them.

Diagnostic pearl: do not call a hyperplastic rest Wilms tumour because the blastema looks cellular or mitotic; judge architecture and interface.

Epithelial-predominant Wilms tumours with metanephric features frequently carry BRAF V600E and TERT promoter mutations (Histopathology 2026).

Diagnostic pearl: a BRAF-mutated paediatric epithelial renal tumour is not automatically metanephric adenoma; examine the whole tumour for blastema and stroma.

• WT1 and PAX8 support Wilms tumour but are not specific; EWSR1 rearrangement alone is not Ewing sarcoma; DSRCT can be WT1+; INI1 loss means rhabdoid tumour.

Diagnostic pearl: do not diagnose monophasic blastemal Wilms tumour on WT1 alone.

• Classic CMN: neonates and young infants, fascicular spindle cells, entrapped tubules, fibromatosis-like, no blastema or nephroblastic epithelium.
• Cellular CMN: dense mitotic spindle cells, ETV6::NTRK3; mimics cellular stromal Wilms.
• Stromal Wilms: smooth or skeletal muscle, sparse tubules or blastema, nephrogenic rests, WT1 and molecular support.

Diagnostic pearl: entrapped native tubules do not make a stromal Wilms tumour; look for genuine nephroblastic epithelium.

• Paediatric cystic nephroma: multilocular, bland lining, thin septa without immature nephroblastic nodules; DICER1.
• CPDN: multilocular with primitive nephroblastic elements in septa, no expansile solid nodules.
• Cystic Wilms tumour: an expansile solid neoplastic component; classify and stage accordingly.

Diagnostic pearl: the presence, extent and location of immature nephroblastic tissue in the septa decide the classification.

Before sampling

• Confirm preoperative chemotherapy; review imaging for multifocality, vessels and nodes; orient; identify sinus and margins.

Key sections

• Capsule and sinus interfaces, sinus veins, perinephric extension, margins, rupture or spill areas, each distinct region, background kidney for rests, every separate nodule.

After chemotherapy

• Map viable vs regressed tumour; estimate regression; proportions of viable blastema, epithelium and stroma; sample residual cellular nodules; search for anaplasia; record extension and margins separately.

Report

• Histology and anaplasia, treatment history, subtype and risk group, stage findings, nodes, margins, rests, protocol-required molecular markers.

Diagnostic pearl: in treated Wilms tumour, inadequate sampling can change the risk group by misjudging residual blastema.

1. Age and treatment status.
2. Developmental morphology: blastema, epithelium, stroma; recognise monophasic tumours.
3. Atypical or monophasic: lineage IHC and molecular tests to exclude other paediatric renal tumours.
4. Anaplasia: strict criteria; focal vs diffuse with adequate sampling.
5. If pretreated: quantify regression and viable blastema, epithelium and stroma.
6. Stage: sinus, perinephric fat, vessels, margins, nodes, rupture or spill.
7. Background kidney: perilobar or intralobar rests; predisposition.
8. Molecular risk: 1q gain, 1p/16q LOH as the protocol requires.

• Untreated: “Wilms tumour (nephroblastoma), favourable histology. Triphasic blastema, epithelial tubules and glomeruloid structures, and stroma; no anaplasia.”
• Focal anaplasia: “Anaplastic cells restricted to sharply demarcated intrarenal focus/foci; no further anaplasia or significant nuclear unrest in the adequately sampled tumour.”
• Diffuse anaplasia: “Nuclear enlargement, hyperchromasia and multipolar mitoses beyond focal criteria.”
• Post-chemotherapy blastemal type: “Wilms tumour, post-chemotherapy blastemal type (SIOP high risk). Regression [%]; viable tumour predominantly blastemal [%]; no diffuse anaplasia.”
• Monophasic biopsy: “Malignant primitive renal neoplasm, favour Wilms tumour. Predominantly blastemal; further IHC and molecular evaluation to exclude other small round cell tumours.”

• Absolute residual blastemal volume (SIOP WT 2001, JCO 2026): independent of percentage across risk groups.
• Biomarker strength differs by COG vs SIOP setting (2026 systematic review).
• Proteogenomics (Nat Commun 2025): molecular heterogeneity beyond morphology.
• Nephrogenic rests (SIOP 2026): no independent adverse effect on relapse-free or overall survival in unilateral tumours, but still relevant for predisposition and contralateral risk.
• Anaplasia (2024 review): focal vs diffuse remain distinct; rigorous criteria and central review are essential.

• Embryonal renal malignancy recapitulating nephrogenesis; triphasic blastema, epithelium and stroma, not all needed.
• Blastemal-predominant mimics small round cell tumours; epithelial mimics metanephric adenoma; stromal mimics CMN; heterologous tissue is common; teratoid and fetal rhabdomyomatous patterns are descriptive.
• Anaplasia = 3× nuclei + hyperchromasia + multipolar mitoses; focal vs diffuse by distribution; diffuse is adverse and TP53-associated.
• WT1 helps but is neither fully sensitive nor specific; PAX8 and keratins support renal epithelial differentiation.
• COG and SIOP differ: post-chemotherapy blastemal predominance is not untreated blastemal predominance; assess regression and viable composition; absolute blastemal volume is emerging.
• 1q gain and 1p/16q loss are prognostic, especially with upfront nephrectomy.
• Nephrogenic rests are precursors with syndromic associations; hyperplastic rests mimic Wilms tumour.
• Framework: embryonal morphology → exclude mimics → anaplasia → treatment-specific classification → molecular and clinical risk.