TFE3-rearranged renal cell carcinomas

• Molecularly defined renal carcinoma driven by TFE3 gene fusions (Xp11.23); formerly Xp11 translocation RCC, part of the MiT family.
• A large share of paediatric RCCs but a small minority of adult RCCs; occurs at any age.
• Classic: large clear to eosinophilic cells in papillary, nested, alveolar or solid growth, often with psammoma bodies; none of these is required.
• Fusion partner shapes morphology and markers, especially cathepsin K.
• PAX8 usually positive; keratins and EMA often weak or negative.
• TFE3 IHC screens but is not specific; molecular confirmation (FISH and/or sequencing) is generally required.
• Cryptic intrachromosomal rearrangements can escape break-apart FISH.
• Behaviour ranges from indolent to aggressive, especially in adults with advanced stage.

Diagnostic pearl: a fusion-defined family of carcinomas, not a single reproducible H&E phenotype.

• Children, adolescents and adults, including older patients; consider it in older adults too.
• Haematuria, pain, mass or incidental finding; some present with nodal or distant metastasis.
• Prior cytotoxic chemotherapy in a subset, especially young patients; mostly sporadic.
• Grossly solid or solid-cystic, tan-yellow to haemorrhagic; calcification and necrosis possible; circumscribed or infiltrative into sinus and fat.
• Gross appearance cannot predict the fusion partner.

Diagnostic pearl: young age is an important clue, but not a requirement.

Architecture

• Mixed papillary, nested, alveolar and solid growth; papillary and nested areas often coexist; fine capillary network around nests.

Cells

• Large polygonal cells with abundant clear, eosinophilic or amphophilic cytoplasm and distinct borders; striking clear-eosinophilic heterogeneity.

Nuclei

• Round to irregular, often prominent nucleoli; pleomorphism mild to marked, varying with fusion.

Psammoma bodies

• Characteristic of ASPSCR1::TFE3; supportive but neither required nor specific.

Other

• Hyalinisation, haemorrhage, necrosis, cystic change, inflammation, calcification or bone.

Diagnostic pearl: large clear cells + papillae + psammoma bodies is a screening pattern, not the definition.

• Papillary / tubulopapillary: may closely resemble PRCC.
• Nested / alveolar: mimics ccRCC; may raise alveolar soft part sarcoma.
• Solid: mimics high-grade ccRCC, oncocytic or unclassified RCC; common in some non-ASPSCR1 fusions.
• Tubular / acinar: may resemble PRCC, CCPRCT or ELOC-RCC.
• Cystic: overlap with other cystic RCCs (especially MED15::TFE3).
• Psammomatous: calcifications may dominate a biopsy.
• Oncocytic: mimics ESC RCC, EVT, oncocytoma or TFEB RCC.
• High grade / sarcomatoid: classic areas may be focal.

Diagnostic pearl: a tubular, cystic, oncocytic or solid tumour can still be TFE3-RCC.

• PAX8: usually nuclear positive; may be weak or heterogeneous; key when keratins are absent.
• TFE3: strong nuclear staining raises suspicion; weak staining is nonspecific; native expression and copy-number gain occur without fusion; negative staining does not exclude.
• Cathepsin K: fusion-dependent (often PRCC::TFE3+, frequently ASPSCR1::TFE3−).
• PanCK / EMA: often weak, focal or negative; this does not mean mesenchymal.
• CK7: usually negative or focal. CD10: frequently positive. AMACR: variable.
• HMB45 / Melan-A: variable, more often in some fusions.
• CAIX: usually negative or limited; diffuse box-like favours ccRCC.

Diagnostic pearl: strong nuclear TFE3 selects tumours for molecular testing; it does not establish the diagnosis.

• PRCC::TFE3: often strong cathepsin K, sometimes Melan-A.
• ASPSCR1::TFE3: frequently cathepsin K negative (unlike alveolar soft part sarcoma with the same fusion).
• Others (e.g. MED15): variable.
• Positive cathepsin K does not prove a fusion; negative does not exclude one; it cannot name the partner.

Diagnostic pearl: a negative cathepsin K in a papillary psammomatous tumour should not lower suspicion of ASPSCR1::TFE3.

• TFE3 (Xp11.23) encodes a bHLH-LZ transcription factor controlling lysosomal, autophagy and growth programmes; fusions keep its DNA-binding domain.
• Recurrent partners: ASPSCR1, PRCC, SFPQ, NONO, MED15, RBM10.
• Rare: CLTC, DVL2, FUBP1, GRIPAP1, KAT6A/B, KHSRP, LUC7L3, MATR3, NEAT1, PARP14, RBMX, SETD1B, ZC3H4 and others.
• In an integrated study of 63 tumours, fusions were found in 57; SFPQ, ASPSCR1, NONO, MED15, PRCC and RBM10 predominated.
• Fusion-associated morphology is probabilistic, not pathognomonic.

Diagnostic pearl: do not infer the partner from H&E or cathepsin K alone.

ASPSCR1::TFE3

• Papillary and nested; large clear to eosinophilic cells, distinct borders; numerous psammoma bodies.
• TFE3 strong; cathepsin K, CK7, EMA and melanocytic markers often negative.
• 2026 series of 30: female predominance, median age about 24, metastasis in 16, 5-year DFS 37.9% and OS 61.4%; necrosis independently predicted shorter DFS. Single-centre selected cohort.

PRCC::TFE3

• Smaller, compact cells; papillary, solid, nested, tubular; fewer psammoma bodies; can resemble PRCC.
• Cathepsin K frequently positive; Melan-A in a subset.

Diagnostic pearl: papillae + clear/eosinophilic cells + psammoma + cathepsin K negative suggests ASPSCR1, but only sequencing names the partner.

• SFPQ::TFE3: solid, nested or alveolar; subnuclear vacuoles giving a secretory look; few papillae.
• NONO::TFE3: papillary, glandular or biphasic; intrachromosomal X inversion; break-apart FISH may be negative or equivocal.
• RBM10::TFE3: intrachromosomal inversion, cryptic on FISH; papillary or solid; melanocytic markers in some.
• MED15::TFE3: often multilocular cystic, mimicking MCRNLMP; cathepsin K and Melan-A may be positive; solid examples exist.
• NEAT1: biphasic, TFEB-like; KAT6A: classic with psammoma; other rare partners lack reliable phenotypes.

Diagnostic pearl: a convincing TFE3-like tumour with negative break-apart FISH should prompt RNA-based testing for cryptic NONO or RBM10 fusions.

• Flanking probes split when TFE3 is rearranged; partner-agnostic; works on FFPE in histologic context.
• Does not name the partner.
• Intrachromosomal inversions may give only subtle separation; truncated nuclei mimic single signals.
• X-linked gene: expected signal numbers depend on sex chromosome complement; aneuploidy complicates scoring.
• Laboratory-specific cutoffs and controls are essential; equivocal splits are not proof.

Diagnostic pearl: a technically adequate negative FISH does not exclude every TFE3 fusion.

Cryptic inversions

• RBM10, NONO, GRIPAP1 and RBMX lie close to TFE3 on Xp; inversions may leave FISH intact.
• Modern Pathology 2025: 20 suspicious MiT tumours with negative/equivocal FISH and TRIM63 overexpression; TFE3 fusions in 12, RBM10 in 8 of these. A preselected cohort.

Testing methods

• RNA-based NGS: names the partner and catches cryptic fusions; needs good RNA and coverage.
• DNA-based NGS: intronic breakpoints may be missed.
• A transcript containing TFE3 must be in frame and biologically credible.

TRIM63 RNA-ISH (331 tumours, 2025)

• Positive in 12/15 TFE3-RCC; specificity 96.2% but PPV 52%; also in 4/6 tubulocystic RCC and 5/13 ESC RCC.
• Useful to select FISH-negative cases for RNA-seq, not to confirm.

Diagnostic pearl: negative FISH should not end the work-up when suspicion is high.

Clear cell RCC

• Both nested with clear cells and a capillary network.
• ccRCC: diffuse box-like CAIX, VHL/3p; TFE3-RCC: limited CAIX, papillae, psammoma, eosinophilic areas.
• Pitfall: native TFE3 nuclear staining occurs in ccRCC without fusion.

Papillary RCC

• PRCC: CK7 and AMACR, +7/+17; TFE3-RCC: mixed clear/eosinophilic cells, psammoma, limited CK7 and keratins.

TFEB-altered RCC

• Shared cathepsin K and melanocytic markers; biphasic morphology is not exclusive to TFEB; confirm the gene.

Diagnostic pearl: a PRCC-like tumour with psammoma bodies, clear cells and unusual keratin expression deserves TFE3 testing.

Alveolar soft part sarcoma

• Same ASPSCR1::TFE3 fusion; lineage decides.
• ASPS: PAX8 and keratin negative, cathepsin K strong, PAS-D crystals, no psammoma; RCC: PAX8+, psammoma, cathepsin K often negative.

TFE3-rearranged PEComa / epithelioid AML

• Epithelioid clear/eosinophilic cells, HMB45/Melan-A, cathepsin K; favours PEComa when PAX8 and keratins are negative.
• Not the same as TSC-driven angiomyolipoma; epithelioid AML can overexpress TFE3 without fusion.

Others

• ESC RCC (stippling, CK20, TSC), EVT (vacuoles, CD117), FH-deficient (FH/2SC), SDH-deficient (SDHB), ALK-rearranged RCC (ALK IHC).

Diagnostic pearl: classification rests on lineage, morphology, setting and molecular findings together, not on the fusion name alone.

1. Suspect: papillary/nested growth, abundant clear or eosinophilic cells, psammoma bodies, or unusual oncocytic, cystic or biphasic phenotypes.
2. Lineage: PAX8, especially if keratins are weak or absent.
3. Screen: TFE3 IHC and cathepsin K; melanocytic markers as needed.
4. Confirm: break-apart FISH; RNA sequencing for the partner.
5. Negative FISH, high suspicion: RNA-based fusion testing; TRIM63 to select.
6. Integrate: call TFE3-RCC only with a credible fusion in a renal epithelial tumour.

On biopsy

• One pattern may be sampled; psammoma may be absent; keratins may be negative.
• TFE3 IHC false positives and FISH false negatives both occur.
• Wording: RCC with features suspicious for TFE3 rearrangement; molecular confirmation recommended.

Diagnostic pearl: an isolated positive TFE3 stain should not reclassify a biopsy.

• Broad spectrum; many localised tumours are cured surgically; adults may behave aggressively at higher stage.
• Key factors: stage, size, nodes, metastasis, necrosis, sarcomatoid or rhabdoid change.
• ASPSCR1::TFE3 linked to adverse behaviour in several cohorts; other fusions heterogeneous.
• WHO/ISUP grading is not validated for each fusion, but atypia and necrosis should be recorded.

Diagnostic pearl: fusion identity complements, never replaces, stage and necrosis.

• ASPSCR1::TFE3 as a higher-risk subtype: frequent metastasis; necrosis independently prognostic (2026, 30 cases).
• Cryptic FISH-negative fusions, especially RBM10::TFE3, increasingly recognised; RNA-seq resolves them.
• TRIM63: helpful adjunct with limited specificity.
• Fusion and therapy: ASPSCR1 tumours may have angiogenic and immune signatures; ICI + VEGFR-TKI activity reported retrospectively; not a validated selection biomarker.
• 151-patient multicentre cohort (2026): 92 metastatic or relapsed; median first-line PFS 6.1 months in 59 treated; ICI/TKI combinations did better than TKI alone, non-randomised.

• Defined by a pathogenic TFE3 fusion, not by a pattern; formerly Xp11 translocation RCC.
• Relatively common in children, uncommon in adults.
• Classic: papillary/nested, clear-eosinophilic cells, psammoma bodies; solid, cystic, oncocytic, tubular and biphasic forms occur.
• ASPSCR1 papillary-psammomatous; PRCC compact and cathepsin K+; SFPQ subnuclear vacuoles; MED15 cystic; NONO and RBM10 cryptic.
• PAX8+, keratins/EMA often weak; cathepsin K negativity does not exclude.
• TFE3 IHC screens; FISH misses cryptic inversions; RNA-seq names the partner; TRIM63 assists.
• ASPS can carry the same fusion: establish lineage.
• Stage and necrosis remain key prognostic factors.