Metanephric adenoma

• Rare, generally benign renal epithelial tumour (about 0.2–0.7% of adult renal epithelial tumours) of small, uniform, primitive-looking cells in densely packed acini and tubules, with variable papillae.
• Minimal atypia, scant cytoplasm, fine chromatin, little or no mitotic activity.
• Glomeruloid structures, short papillae, microcysts and psammoma bodies are common.
• Phenotype: WT1+, CD57+, PAX8+; CK7 and AMACR negative or focal.
• BRAF p.V600E in about 80–90%; V600E-negative tumours may carry RET, ALK, ROS1 or BRAF fusions (2026).
• Rare challenging tumours overlap with epithelial-predominant Wilms tumour.

Diagnostic pearl: a cellular but cytologically bland tumour of miniature acini and tubules, not simply a renal tumour with a BRAF mutation.

• Mostly middle-aged adults, also children and older patients; female predominance.
• Often incidental; haematuria, pain or a mass; occasionally polycythaemia.
• Solitary, well circumscribed, unencapsulated, tan to grey-white, mostly solid; haemorrhage, cysts, calcification possible; interface may be irregular.

Diagnostic pearl: imaging and gross appearance cannot reliably separate MA from low-grade RCC.

Architecture

• Densely packed small round acini and tubules with tiny lumina; some look solid.
• Straight, curved, branched or angulated tubules merging into compact areas.

Cells

• Small cuboidal cells, very scant cytoplasm, high N:C ratio, uniform round nuclei, fine chromatin, inconspicuous nucleoli.

Stroma and extras

• Delicate, oedematous, fibrous or hyalinised stroma; glomeruloid structures, papillae, psammoma bodies, microcysts, occasional foamy macrophages.

Diagnostic pearl: it can look highly cellular and primitive, but the nuclei are strikingly uniform with few or no mitoses.

• Compact acinar: classic; tightly packed acini can look like a solid sheet at low power.
• Branching tubular: complex, angulated, interconnected tubules, often near oedematous stroma.
• Solid-like: very dense acini; search for miniature lumina; not blastema.
• Trabecular / cord-like: collapsed or tangentially cut tubules; broad atypical sheets are not typical.
• Glomeruloid: tufts in dilated tubules, an important clue.
• Papillary: short papillae with thin cores; can mimic PRCC.
• Microcystic / cystic: small dilated acini, occasionally larger cysts.
• Psammoma bodies: may be numerous; not specific.

Diagnostic pearl: before calling an area solid, look for tiny lumina; papillae and psammoma do not establish PRCC.

• Stromal oedema: pseudoinfiltrative or reticular look.
• Hyalinisation / fibrosis: septa separating nests, with calcification.
• Foamy macrophages: occasional; extensive collections overlap with PRCC.
• Eosinophilic change: focal only; an oncocytic tumour is not MA because BRAF is altered.
• Mitoses: usually few; rare genetically confirmed MA-like tumours show more, overlapping with epithelial Wilms tumour.

Diagnostic pearl: bland nuclei and the acinar architecture matter more than absolute mitotic inactivity.

• WT1: strong diffuse nuclear; also in epithelial Wilms tumour.
• CD57: usually positive, often membranous; occasional negatives.
• PAX8: usually positive.
• BRAF V600E (VE1): positive in about 80–90%, diffuse cytoplasmic; a negative result does not exclude MA.
• CK7, AMACR: negative or focal; diffuse staining favours PRCC.
• CD10, EMA: usually negative or limited.
• ALK: negative in most; may flag rare fusion-positive tumours.

Classic four-marker profile (Cheng, Mod Pathol 2015)

• WT1+ / CD57+ / CK7− / AMACR− in 31 of 37 tumours first called MA; two were reclassified as PRCC; cytogenetics helped discordant cases.

Diagnostic pearl: start with WT1 + CD57 + CK7 + AMACR, then BRAF VE1.

BRAF V600E

• Constitutive MAPK activation; 80–90% (rarely V600D or V600K).
• MA lacks the +7/+17 of PRCC.
• Not unique: BRAF-mutant epithelial Wilms tumours exist; wild-type BRAF does not exclude MA.

BRAF V600E-negative MA (Zhao, AJSP 2026, 7 cases)

• Fusions: CCDC6::RET 2, ANKRD26::RET 1, STRN::ALK 2, RDX::ROS1 1, CUX1::BRAF 1.
• Typical MA morphology; leaf-like branching dilated tubules around compact acini in 4; thyroid follicle-like or microcystic/reticular in 3.
• All WT1/CD57 diffuse, VE1 negative, CK7/AMACR largely negative; disease-free over 14–115 months.
• No fusions in 7 BRAF-mutant comparators; small cohort.

Diagnostic pearl: BRAF-negative MA is not necessarily unclassified; RNA sequencing can find kinase fusions.

• Driver-based view: ALK-rearranged RCC is a defined entity, MA-like ALK-RCCs were reported before, so an ALK fusion supports ALK-RCC.
• Integrated view: two 2026 STRN::ALK tumours kept classic MA morphology and WT1/CD57, lacked CK7/AMACR and did well; the authors called them MA with an alternative driver.
• The 2020 ALK-RCC series also included MA-like tumours with WT1 and ALK coexpression, so no single marker settles it.
• Unresolved: does every renal epithelial tumour with an oncogenic ALK fusion belong to ALK-RCC, or can classic MA carry ALK fusions?

Diagnostic pearl: an ALK fusion in an MA-like tumour calls for integrated reassessment, not automatic classification from either H&E or the molecular result alone.

Papillary RCC (key adult mimic)

• Larger cells with more cytoplasm, variable nucleoli; papillary, tubular, solid.
• WT1 and CD57 negative or focal; CK7 and AMACR positive; BRAF uncommon; +7/+17.
• Look for miniature acini, primitive nuclei; use the four-marker panel, VE1 and copy number for discordant cases.

Papillary adenoma

• Low-grade papillary/tubular lesion ≤15 mm, CK7/AMACR+, may share +7/+17.
• Size does not separate MA from papillary adenoma; the phenotype does.

Diagnostic pearl: a papillary lesion with psammoma bodies can be MA; integrate cytology, phenotype and molecular pattern.

• Most consequential paediatric differential.
• Wilms: usually children, variable epithelial patterns, blastema (may be unsampled), atypia, more mitoses; WT1 often positive; CD57 variable; BRAF V600E in a subset.
• MA-like areas occur within Wilms tumour; Histopathology 2026 described BRAF V600E and TERT promoter-mutated epithelial Wilms tumours with metanephric features.
• Adult Wilms tumours can arise from MA (genetic evidence, 2022).
• Sample extensively, search for blastema and malignant epithelium, assess proliferation; seek expert or molecular help when uncertain.

Diagnostic pearl: BRAF V600E is not a guarantee of benignity; morphology and sampling remain essential.

ALK-rearranged RCC

• Overlapping small acini, glomeruloid tufts, psammoma.
• Favour MA: diffuse WT1/CD57, CK7/AMACR negative, BRAF V600E.
• Raise ALK-RCC: diffuse CK7/AMACR, mucin or signet-ring cells, heterogeneity, ALK staining.
• Classic MA phenotype does not absolutely exclude an ALK fusion (2026).

Metanephric family

• Metanephric adenofibroma: MA-like epithelium plus substantial spindle-cell stroma.
• Metanephric stromal tumour: spindle cells with concentric cuffing (onion-skinning) around tubules and vessels; distinguish from congenital mesoblastic nephroma.

Diagnostic pearl: extensive spindle-cell stroma means a mixed metanephric tumour, not conventional MA.

1. Architecture: packed miniature acini and tubules, glomeruloid tufts, papillae, psammoma.
2. Cytology: uniform small nuclei, fine chromatin, scant cytoplasm, few mitoses.
3. IHC: WT1, CD57, CK7, AMACR.
4. BRAF V600E (VE1 or sequencing).
5. Discordance (diffuse CK7/AMACR, atypia, unusual age or pattern, VE1 negative): further testing.
6. Fusion testing selectively in VE1-negative tumours.
7. Exclude Wilms tumour in children or proliferative tumours.

On biopsy

• Compact acini mimic solid PRCC; papillary areas mimic papillary adenoma/PRCC; Wilms tumour may be under-sampled.
• VE1 positivity supports MA but does not exclude epithelial Wilms tumour; VE1 negativity does not exclude MA.
• Ambiguous: low-grade renal epithelial neoplasm with metanephric adenoma-like features.

• Benign; excellent outcome after excision.
• Apparent metastasis should prompt diagnostic reassessment (overlapping tumours or unusual biology).
• RCC nuclear grading is not applicable; BRAF mutation is not a malignancy marker.
• Behaviour of fusion-positive MA is favourable so far, but follow-up is limited.

Diagnostic pearl: unusual morphology, discordant IHC or metastasis warrant review rather than presuming conventional MA.

• Kinase fusions (RET, ALK, ROS1, BRAF) in BRAF V600E-negative MA; leaf-like and follicle-like patterns.
• STRN::ALK in classic MA blurs the boundary with ALK-RCC; unresolved.
• BRAF/TERT-mutated epithelial Wilms tumours with metanephric features show BRAF does not settle MA versus Wilms.
• Targeted testing: the four-marker phenotype usually suffices; reserve RNA-NGS for VE1-negative or discordant tumours.

• Benign tumour of small uniform cells in packed acini and tubules; adults, female predominance.
• Packed tubules can look solid; glomeruloid tufts, papillae, microcysts and psammoma are compatible.
• WT1+/CD57+/CK7−/AMACR− is the classic profile; PAX8+.
• BRAF V600E in 80–90%; negative VE1 does not exclude; kinase fusions in some negatives.
• Solid-pattern PRCC is the key adult mimic; epithelial Wilms tumour the key paediatric mimic.
• BRAF does not reliably separate MA from epithelial Wilms tumour.
• STRN::ALK in MA-like tumours is an unresolved classification boundary.