Metanephric adenofibroma and metanephric stromal tumour

• Metanephric stromal tumour (MST): rare, benign renal mesenchymal neoplasm of bland spindle or stellate stromal cells that characteristically entrap native tubules and glomeruli.
• Metanephric adenofibroma (MAF): rare, benign biphasic neoplasm with a metanephric adenoma-like epithelial component and a stromal component essentially identical to MST.
• Both belong to the metanephric family.

Shared features

• Bland spindle-cell stroma with alternating hypercellular and hypocellular areas.
• Concentric stromal cuffing around entrapped tubules (onion-skin).
• Intratumoral small-vessel angiodysplasia.
• Occasional heterologous cartilage or glia.
• Frequent stromal CD34; recurrent BRAF p.V600E; generally benign.

Fundamental distinction

• MST: neoplastic stroma + entrapped non-neoplastic epithelium.
• MAF: neoplastic stroma + genuine neoplastic metanephric epithelium.

Diagnostic pearl: tubules inside a spindle-cell tumour do not make it MAF. The question is whether the epithelium is entrapped native tissue or a true neoplastic metanephric component.

MST

• Mainly infancy and early childhood; mean age about 2 years in the original 31-case series.
• Abdominal mass; occasionally haematuria or hypertension. Adult cases are uncommon but documented.
• Firm, pale tan-white to grey-white mass, often centred in the medulla; lobulated or multinodular; small smooth-walled cysts; usually unencapsulated with variable entrapment of renal tissue.

MAF

• Mostly children, adult cases documented; abdominal mass, haematuria or incidental; polycythaemia reported.
• Well circumscribed but not necessarily encapsulated; tan-white to grey-white, solid with small cysts; heterogeneous cut surface reflecting the two components.

Diagnostic pearl: both resemble more common paediatric renal tumours on imaging and gross examination; the distinction is microscopic.

Cells

• Bland spindle or stellate cells, small elongated nuclei, fine chromatin, inconspicuous nucleoli, scant pale cytoplasm.
• Very low mitotic activity; no significant pleomorphism in conventional cases.

Growth pattern

• Short intersecting or irregular fascicles; alternating cellularity; nodular or lobulated at low power; stromal cells envelop pre-existing renal structures.

Matrix

• Variable collagen, focal myxoid or oedematous areas, sclerosis or hyalinisation, collagen bands separating cellular areas.

Additional

• Entrapped tubules and glomeruli, peritubular collarettes, abnormal small vessels, occasional heterologous elements.

Diagnostic pearl: bland spindle cells + alternating cellularity + entrapped nephrons + peritubular cuffing should immediately raise MST or the stroma of MAF.

• Concentric layers of spindle cells around entrapped tubules, forming ring-like collarettes; the single most characteristic stromal feature.
• Cells align tangentially; rings may be tight and compact or looser and collagenous; tubules may be compressed or distorted.
• Focal or widespread, most conspicuous in cellular areas; not every tubule shows it; fibrosis may obscure collarettes.

Interpretation

• Strongly supports metanephric stromal differentiation.
• Particularly useful against congenital mesoblastic nephroma.
• Read together with the vascular changes and overall phenotype.

Diagnostic pearl: an excellent clue, but its absence in a small biopsy does not exclude MST or MAF.

Intratumoral angiodysplasia

• Small arteries and arterioles with irregular wall thickening.
• Enlarged, epithelioid vascular smooth muscle cells; disorganised walls; concentric or asymmetric changes.

Juxtaglomerular cell hyperplasia

• Entrapped glomeruli may show prominent, hyperplastic juxtaglomerular cells.

Clinical associations

• Some patients are hypertensive.
• A minority of historical MSTs had florid vascular changes with extrarenal vasculopathy and real morbidity; this is not malignant transformation.

Limitations

• Subtle or absent in limited tissue; best seen in well-preserved intratumoral arterioles.
• Do not mistake nonspecific vascular hyalinisation for angiodysplasia.

Diagnostic pearl: onion-skinning plus angiodysplasia is far more persuasive than bland spindle-cell morphology alone.

• Cartilage: focal mature or immature islands within bland stroma; supportive in the right context; not sarcomatous.
• Glia: rare foci in the stroma; may need focused ancillary testing.
• Myxoid areas: stellate cells in basophilic matrix; overlap with other paediatric myxoid tumours; vascular and peritubular changes help.
• Dense collagenisation: hypocellular sclerotic areas can look fibroma-like; entrapped tubules may be hard to find.
• Nodular growth: alternating cellularity gives a characteristic low-power pattern, useful when cuffing is focal.

Diagnostic pearl: heterologous cartilage or glia can occur in a benign metanephric stromal tumour and does not mean aggressive mesenchymal differentiation.

• Multinodular spindle-cell proliferation with native renal structures entrapped throughout.
• Border may be sharp yet irregular or scalloped; MST can interdigitate with renal tissue; entrapment is not destructive invasion.
• Entrapped tubules are dilated, distorted or compressed, often with cuffs, but do not form large autonomous MA-like nodules.
• Entrapped glomeruli, sometimes deep in the lesion, with juxtaglomerular hyperplasia.
• Numerous epithelial profiles do not by themselves make a tumour biphasic; entrapped tubules can be abundant.

Diagnostic pearl: a bland CD34+ stromal neoplasm with prominent onion-skinning, angiodysplasia and scattered native glomeruli strongly favours MST.

Epithelial component

• Resembles metanephric adenoma: small uniform cuboidal cells, scant cytoplasm, compact tubules and acini with tiny lumina.
• Focal papillary or glomeruloid structures; psammoma bodies; uniform nuclei, inconspicuous nucleoli.

Stromal component

• Same as MST: bland spindle cells, alternating cellularity, myxoid or collagenous areas, onion-skinning, angiodysplasia, possible heterologous elements.

Distribution

• Components intimately admixed or epithelial nodules surrounded by stroma; proportions vary, some areas nearly purely stromal.

Recognising genuine epithelial neoplasia

• Compact expansile epithelial nodules; densely crowded primitive acini not explained by pre-existing tubules; papillary or glomeruloid formations of uniform metanephric cells.

Diagnostic pearl: MAF is not simply MST with many tubules; it requires a metanephric adenoma-like neoplastic epithelium.

Diagnostic pearl: the stromal components are highly similar; the real task is proving a genuine neoplastic epithelial component.

• CD34: diffuse or patchy; maps the stroma; a negative result does not exclude either.
• WT1: nuclear in MAF epithelium; entrapped native epithelium can also be WT1+, so morphology must prove neoplasia.
• PanCK, PAX8: highlight MAF epithelium and also entrapped tubules in MST; proving epithelium does not prove MAF.
• BRAF VE1: supports a BRAF-mutated metanephric tumour; convincing staining in the spindle cells marks them as neoplastic; negativity does not exclude.

Diagnostic pearl: WT1+ epithelium with CD34+ stroma is a helpful map of MAF, but morphology must show the epithelium is neoplastic.

• BRAF p.V600E constitutively activates RAS-RAF-MEK-ERK; dominant driver of MA and frequent in MST and MAF.

MST

• Human Pathology 2016: 11 of 17 (65%) MSTs BRAF V600E positive.
• None of 22 congenital mesoblastic nephromas or 6 ossifying renal tumours of infancy had a BRAF exon 15 mutation.

MAF

• BRAF V600E found in both epithelial and stromal compartments, supporting a common clonal origin.
• Exact frequency less secure; molecular cohorts are small.

Limits

• BRAF-negative MST and MAF exist; VE1 is an adjunct, not a criterion.
• BRAF V600E is not exclusive to metanephric tumours; reconcile with morphology and lineage.

Diagnostic pearl: the same BRAF driver in both MAF compartments supports one neoplasm rather than a coincidental mix.

• Classic CMN: fibromatosis- or leiomyoma-like fascicles permeating the kidney with entrapped tubules, but without collarettes, angiodysplasia and metanephric nodularity.
• Cellular CMN: dense, mitotically active, infantile fibrosarcoma-like; ETV6::NTRK3 common.
• Onion-skinning and angiodysplasia favour MST/MAF; high cellularity and brisk mitoses raise cellular CMN; molecular testing can decide.

Diagnostic pearl: entrapped tubules do not separate MST from classic CMN; collarettes and angiodysplasia do.

Overlap with MAF

• Primitive epithelium, spindle stroma, tubules and glomeruloid forms, paediatric age, WT1 in epithelium.

Favours MAF

• Uniformly bland MA-like epithelium; no convincing blastema; minimal atypia and proliferation; onion-skinning and angiodysplasia; CD34+ stroma; BRAF V600E.

Favours Wilms tumour

• Unequivocal blastema (expanding aggregates of small round blue cells); more variable epithelial differentiation; mitoses and atypia; stroma not following the metanephric pattern.

Caveat

• Historical MAF series included mitotically active lesions and composite MAF/Wilms or MAF/tubulopapillary carcinoma; sample the whole lesion when anything is atypical.

Diagnostic pearl: do not call a biphasic paediatric renal tumour MAF until Wilms tumour has been excluded by adequate sampling.

CCSK

• Uniform cells in cords or nests with a delicate branching chicken-wire capillary network.
• Myxoid or sclerotic stroma; spindle, epithelioid, palisading and other patterns; deceptively bland nuclei despite malignant behaviour.
• BCOR and cyclin D1 nuclear staining; BCOR internal tandem duplication in many; YWHAE::NUTM2 or other alterations in some.

Favours MST

• Entrapped tubules and glomeruli, peritubular cuffing, angiodysplasia, CD34, BRAF V600E.

Diagnostic pearl: a bland paediatric renal spindle-cell tumour is not automatically benign; vascular pattern, entrapment and molecular findings decide.

• Metanephric adenoma: epithelial tumour without a substantial neoplastic stroma; WT1/CD57+, BRAF V600E; a prominent spindle-cell component with collarettes indicates MAF.
• Mixed epithelial and stromal tumour: adults, usually women; cysts and tubules with ovarian-type stroma, ER/PR+; no onion-skinning, angiodysplasia or MA-like nodules.
• Angiomyolipoma: spindle or myoid areas, fat, dysmorphic thick-walled vessels; smooth muscle and melanocytic markers. Collarettes and CD34 favour MST/MAF.

Diagnostic pearl: not every biphasic epithelial-stromal renal tumour is MAF; the epithelium must be MA-like and the stroma characteristic.

1. Stromal phenotype: bland spindle or stellate cells, alternating cellularity, nodular configuration.
2. Hallmark features: onion-skinning, angiodysplasia, juxtaglomerular hyperplasia, heterologous cartilage or glia.
3. Is the epithelium neoplastic? Entrapped native tubules versus autonomous MA-like proliferation.
4. Compartment IHC: CD34 for stroma; WT1, PAX8, CD57, keratins for epithelium; CK7/AMACR if RCC is in the differential.
5. BRAF: VE1 or sequencing, especially in unusual or limited cases.
6. Exclude paediatric mimics: CMN, Wilms tumour, CCSK according to the dominant histology.
7. Classify: stroma + entrapped epithelium → MST; stroma + neoplastic metanephric epithelium → MAF; blastema or other atypical component → investigate before a benign diagnosis.

• An MST core with many entrapped tubules can look biphasic; a MAF core may sample only stroma.
• MA-like nodules, onion-skinning and angiodysplasia may be focal or absent; CD34 may be patchy; BRAF-negative cases exist.
• Biopsies may miss blastemal or atypical Wilms components.

Suggested wording

• Convincing MST: “Metanephric stromal tumour. Bland spindle-cell proliferation with peritubular concentric cuffing and vascular alterations; no neoplastic epithelial component in the examined material.”
• Convincing MAF: “Metanephric adenofibroma. Biphasic proliferation of metanephric adenoma-like epithelium and characteristic bland metanephric stroma.”
• Limited or equivocal: “Renal spindle-cell neoplasm with features suggestive of metanephric stromal tumour. Limited sampling prevents exclusion of metanephric adenofibroma or other paediatric renal neoplasms.”

Diagnostic pearl: on biopsy, MST versus MAF may depend more on what has not been sampled than on what is present.

• MST: benign; no recurrence or metastasis after surgery in the founding 31-case series; a small subset has vascular or hypertension-related complications.
• MAF: pure conventional tumours are benign with excellent outcomes after resection.
• Composite tumours with Wilms tumour or another malignant epithelial component are classified and managed by that component.
• Recognition avoids unnecessary chemotherapy; no carcinoma-type nuclear grading applies.

Diagnostic pearl: the main danger is misclassification as a malignant paediatric renal tumour, not intrinsic aggressiveness.

• Metanephric family: BRAF activation in MA, MST and MAF; V600E in MST shows the alteration is not confined to epithelium; shared mutation in both MAF compartments supports clonality. Shared BRAF does not make the three tumours interchangeable.
• Adult cases: adult MST can mimic renal fibroma or solitary fibrous tumour; adult MAF can mimic MEST. Peritubular and vascular changes help at any age; age refines, it does not exclude.
• BRAF-negative tumours: RET, ALK, ROS1 and BRAF fusions were found in V600E-negative MA (2026); they have not been shown in MST or MAF and should not be extrapolated.
• Morphology first: MST versus MAF is architectural and compartmental; molecular testing helps most against CMN and other paediatric spindle-cell malignancies.

Diagnostic pearl: neither BRAF positivity nor a CD34+ spindle-cell population alone establishes MAF.

• Distinct but closely related benign metanephric neoplasms: MST mesenchymal, MAF biphasic.
• Their spindle-cell stroma is essentially identical, with nodular alternating cellularity.
• Onion-skinning, angiodysplasia and juxtaglomerular hyperplasia strongly support the diagnosis; cartilage or glia may occur.
• CD34 marks the neoplastic stroma; WT1 is positive in MAF epithelium, generally negative in the stroma.
• PAX8 and keratins mark both neoplastic and entrapped epithelium.
• BRAF V600E is recurrent in both and shared by both MAF compartments; negativity does not exclude.
• Main mimics: CMN (spindle), Wilms tumour (biphasic), CCSK (bland paediatric spindle).
• Pure MST and MAF are benign.